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S0014483520305492 | Retinitis pigmentosa is a collection of heterogenous genetic retinal disorders resulting in cumulative retinal deterioration involving progressive loss of photoreceptors and eventually in total blindness . Oxidative stress plays a central role in this photoreceptor loss . Gypenosides are the main functional component isolated from the climbing vine | Gypenosides reduce photoreceptor death in a zebrafish retinitis pigmentosa RP model. Gypenosides enhance antioxidative capacity in a zebrafish RP model. Gypenosides suppress ROS production and inflammation in a zebrafish RP model. Gypenosides have therapeutic potential for retinal degeneration. |
S0014483520305510 | This human primary co culture model using human retinal microvascular endothelial cells and human retinal pericyte cells aims to improve current understanding of the cellular changes occurring in the retinal microvasculature during diabetic retinopathy . Currently patients often present in clinic with late stage DR only when vision becomes impaired . Therefore new strategies for earlier detection in clinic combined with novel pharmaceutical and cellular interventions are essential in order to slow or halt the progression of DR from background to sight threatening stage . This co culture model can be used as a simple replicable in vitro tool to discover and assess novel drug therapies and improve fundamental understanding of alterations to cell behaviour in the human retinal microvasculature during DR . | hREC and hRP were successfully cultured long term without dedifferentiation. In vitro hypoxic and hyperglycaemic conditions induced a diabetic like environment. The endothelial barrier was maintained in healthy and diabetic long term culture. hRP formed physical cytoplasmic contacts with hREC through pores in the BM mimic. The angiogenic response profile was different between mono and co culture. |
S0014483520305522 | Most patients with chronic dry eye disease have episodic flares which can be triggered by a variety of activities and environmental stresses . These flares are typically associated with rapid exacerbation of discomfort symptoms followed by prolonged elevation of inflammation . In an acute flare ocular surface inflammation begins with a nonspecific innate immune response in some cases followed by a slower but more specific adaptive immune response . At the ocular surface epithelial cells are central to the innate immune response and we discuss their role in DED flares alongside the other core components . Epithelial cells and other cells of the innate response trigger flares in response to increased osmolarity detected via pattern receptors on their cell surface . Ultimately downstream signaling pathways activate innate and adaptive immune responses with consequent inflammation and symptoms . In chronic DED pathogenic T cells have infiltrated the ocular surface tissues . The established adaptive immune response is likely to lead to flare ups at lower thresholds of stress with inflammation maintained over a longer period . Increased understanding of the inflammatory cascades activated during a flare may guide management and improve outcomes . | Episodic inflammatory flares occur in most patients with chronic dry eye disease. Flares typically show rapid onset followed by prolonged exacerbation of symptoms. Flares result from complex inflammatory cascades. Increased understanding of flares may guide management and improve outcomes. |
S0014483520305534 | The lacrimal functional unit regulates tear production composition distribution and clearance to maintain a stable protective tear layer that is essential for maintaining corneal epithelial health . Dysfunction of the LFU commonly referred to as dry eye leads to increased tear osmolarity and levels of inflammatory mediators in tears that cause ocular surface epithelial disease termed keratoconjunctivitis sicca . Corneal changes in KCS include glycocalyx loss barrier disruption surface irregularity inflammatory cytokine chemokine production cornification and apoptosis . These can reduce visual function and the increased shear force on the corneal epithelium can stimulate nociceptors sensitized by inflammation causing irritation and pain that may precede frank clinical signs . Therapy of keratoconjunctivitis sicca should be tailored to improve tear stability normalize tear composition improve barrier function and minimize shear forces and damaging inflammation to improve corneal epithelial health . | This review highlights the effects of dry eye on the corneal epithelium. The corneal epithelium has an essential function of protecting the cornea from environmental insults and inflammation. It also shields the nociceptors in the cornea from damage and sensitizing agents. Reduced volume and tear compositional changes in dry eye cause dysfunction and death of the corneal epithelium that alters barrier function and differentiation and stimulates inflammation. KCS degrade visual function and cause eye dryness and pain sensations. |
S0014483520305546 | Transient intraocular pressure elevations are likely to occur in certain forms of glaucoma and after intravitreal injections to treat various retinal diseases . However the impact of these transient IOP elevations on the physiology of individual retinal ganglion cells is unknown . In this report we explore how transient IOP elevations in mice affect RGC physiology RGC anatomy and retinal arteriole and capillary structure . Transient IOP elevation was induced in 12 week old wild type C57BL6J mice by injecting sodium hyaluronate into the anterior chamber . IOP was measured immediately after the injection and again 1 and 7 days later . Average peak IOP after injection was 50mmHg and subsequent IOPs returned to normal . RGC physiology was assessed with a multielectrode array by calculating a spike triggered average at the same time points . RGC counts and retinal vascular structure were assessed 14 days after injection with immunohistochemistry to label RGCs and blood vessels . Transient IOP elevation caused a marked reduction of scotopic STA presence and delayed center and surround STA peak times that did not recover . Transient IOP elevation also caused a reduced photopic receptive field size and spontaneous firing rate both of which showed some recovery with time . Transient IOP elevation also induced vascular remodeling the number of capillary branches was decreased within the superficial and intermediate vascular plexi . RGC counts retinal arteriole diameter and deep capillary plexus branching were unaffected . These previously unappreciated findings suggest that transient IOP elevation may cause unrecognized and potentially long term pathology to RGCs and associated neurovascular units which should be accounted for in clinical practice . | We transiently elevated IOP to high levels in mice. We assessed RGCs function at three time points after IOP elevation. We assessed retinal vascular anatomy and RGC numbers at one time point after IOP elevation. Multiple aspects of RGC function were abnormal after IOP elevation and these had different patterns of recovery with time. Specific retinal vascular plexi had reduced numbers of capillary branches. |
S001448352030556X | The highly innervated cornea is susceptible to nerve loss secondary to systemic diseases such as diabetes and metabolic disturbances caused by high fat diet . In this study we characterize the effect of high fat diet on the mouse corneal neuroimmune phenotype including changes to corneal nerve density and resident immune cells alongside the clinical assessment of corneal thickness and endothelial cell density . Male C57Bl6 J mice aged 10 weeks were fed a high fat diet or control diet for 16 weeks . At the study endpoint metabolic parameters were measured to confirm metabolic disturbance . Clinical imaging of the anterior segment was performed using optical coherence tomography to measure the corneal epithelial and stromal thickness . Corneal sensory nerves were visualized using flatmount immunostaining and confocal microscopy . The topographical distribution and density of sensory nerves BIII tubulin High fat diet mice had significantly higher blood HbA1c higher body weight a higher percentage of body fat and elevated fasting glucose compared to the control diet mice . Corneal epithelial and stromal thickness was similar in both groups . The sum length of the basal nerve plexus was lower in the central and peripheral cornea of mice fed a high fat diet . In contrast the sum length of superficial nerve terminals was similar between groups . Epithelial immune cell density was two fold higher in the central corneas of high fat diet mice compared to control diet mice . IBA1 Together with corneal neuropathy corneal immune cells in mice fed a high fat diet were differentially affected depending on their topographical distribution and location within cornea and appeared in closer proximity to epithelial and stromal nerves suggesting a local neuroimmune disruption induced by systemic metabolic disturbance . | Research highlights Jiao et al. The effect of high fat diet induced metabolic disturbance on corneal neuroimmune phenotype. High fat diet in mice differentially affects corneal sensory nerve plexi. Intraepithelial CD45. cells and macrophages are affected in the corneas of high fat diet mice. Endothelial cells and corneal thickness remain unchanged in the high fat diet mice. The changes in the corneal immune cells correlate with metabolic disturbance. |
S0014483520305704 | In piglets we tested the applicability of digital video microscopy and diffuse reflectance spectroscopy for non invasive assessments of limbal and bulbar conjunctival microcirculation . | Digital microscopy and spectroscopy can record microvascular data from conjunctiva. Analyzed results quantify oxygen delivery from capillaries. Capacity for capillary oxygen delivery is higher in limbus compared with bulbus. |
S0014483520305820 | Although the triggers causing angiogenesis in the context of neovascular age related macular degeneration are not fully understood oxidative stress is likely involved . Oxidative stress in the eye can occur through exposure of macular tissues to sunlight and local or systemic exposure to oxidative stressors associated with environmental or lifestyle factors . Because trace elements have been implicated as regulators of oxidative stress and cellular antioxidant defense mechanisms we hypothesized that they may play a role as a risk factor modifying the progression toward nAMD . | Analyses of 16 plasma trace element levels in neovascular AMD patients vs controls. Barium and cadmium are elevated in 236 cases compared to 236 age matched controls. Chromium levels are reduced in the neovascular AMD patients compared to controls. Environmental and lifestyle factors affect trace element levels in neovascular AMD. Trace elements provide a potential target for novel strategies for AMD prevention. |
S0014483520305844 | The Descemet s membrane and the lens capsule are two ocular basement membranes that are essential in maintaining stability and structure of the cornea and lens . In this study we investigated the proteomes and biomechanical properties of these two materials to uncover common and unique properties . We also screened for possible protein changes during diabetes . LC MS MS was used to determine the proteomes of both BMs . Biomechanical measurements were conducted by atomic force microscopy in force spectroscopy mode and complemented with immunofluorescence microscopy . Proteome analysis showed that all six existing collagen IV chains represent 70 of all LC protein and are thus the dominant components of the LC . The DM on the other hand is predominantly composed of a single protein TGF induced protein which accounted for around 50 of all DM protein . Four collagen IV family members in DM accounted for only 10 of the DM protein . Unlike the retinal vascular BMs the LC and DM do not undergo significant changes in their protein compositions during diabetes . Nanomechanical measurements showed that the endothelial epithelial sides of both BMs are stiffer than their respective stromal anterior chamber sides and both endothelial and stromal sides of the DM were stiffer than the epithelial and anterior chamber sides of the LC . Long term diabetes did not change the stiffness of the DM and LC . In summary our analyses show that the protein composition and biomechanical properties of the DM and LC are different | Using mass pectrometry the protein composition of the lens capsule LC and the Descemet s membrane DM was determined. Atomic Force Microscopy was utilized to investigate the biomechanical properties of the LC and the DM. The protein composition of the LC and DM show significant differences. The DM is stiffer than the LC. The protein composition and the stiffness of DM and LC do not change following long term diabetes. |
S0014483520306072 | Pseudoexfoliation syndrome is the most common cause of secondary open angle glaucoma worldwide . Single nucleotide polymorphisms in the gene Lysyl oxidase like 1 | LOXL1 expression is decreased in Pseudoexfoliation Glaucoma. Decreased expression of LOXL1 is orchestrated via DNA methylation. Global methylation and LOXL1 promoter methylation are increased in PXFG. The methylation inhibitor 5 azacytidine restores LOXL1 expression. |
S0014483520306151 | To investigate the optical transmittance and ultrastructure of small incision lenticule extraction derived lenticules preserved via three different methods . A total of 90 lenticules obtained from myopic patients undergoing SMILE surgery were divided into control and experimental groups . Fresh lenticules served as the control . The preserved lenticules of the experimental group were randomly divided into three subgroups according to different storage conditions anhydrous glycerol silicone oil and allochroic silica gel groups . Optical transmittance was evaluated histological changes were analysed by haematoxylin eosin staining and collagen fibril densities and necrotic response were assessed via transmission electron microscopy at 48h 14 days and 4 weeks . After storage for 4 weeks the mean percentage transmittance values in glycerol and silicone oil groups significantly decreased but the lenticules preserved in silica gel remained unchanged when compared with the control lenticules . In all the groups HE staining results showed a regular arrangement of collagen fibers with a few keratocytes and several cavitation bubbles . TEM revealed that the fibril densities in the glycerol group 273.7031.42 m All the three agents namely glycerol silicone oil and silica gel could be used for lenticule preservation . Silica gel facilitates better maintenance of optical transmittance than the other two agents . | This study compared optical transmittance and ultrastructure of SMILE derived lenticules subjected to three different preservative methods. Glycerol silicone oil and silica gel could be used for lenticule preservation. Silica gel facilitates better maintenance of optical transmittance. |
S0014488618303236 | To establish an animal model for posttraumatic stress disorder in burn injured patients . Thermal injured mice with 15 total body surface area were subjected to a series of neurobehavioral tests at 1 and 3months postburn . Brains were collected for analysis of key molecules expression spleens for T cell function analysis and blood for biochemistry and hormones detection . Comparison with sham mice burn mice showed extremely high locomotion in homecage open field and forced swimming tests indicating a hyper arousal state . Burn mice exhibited improved spatial memory in Morris Water Maze test and heightened context fear memory in context fear conditioning suggesting re experiencing behavior . Although burn mice showed pronounced passive avoidance in the step through test their active avoidance capability in response to the conditional stimulus in the shuttle box test was relatively deteriorated . Likewise the retention of cue feared memory was impaired in fear conditioning test . The above negative alterations in mood were recapitulated in open field test in which the burn mice displayed an anxiety like behavior with less time spent in the center . However no sign of depression was found in the forced swimming and sucrose preference tests . The negative mood of burn mice was reinforced by a deficit in sociality and preference for social novelty in social interaction test . These neurobehavioral alterations were associated with an increased expression of brain derived neurotrophic factor along with a remarkable microgliosis and a moderate astrocytosis in the brain of burn We conclude that even mild burn injury could lead to long lasting cognitive and effective alterations in mice . These findings shed light on the interactions among neuropsychology neurobiology and immunology throughout the recovery period of burn injury . | Burn mice manifested long lasting improved spatial and contextual fear memories corresponding to the re experiencing symptom in PTSD. The worsened coping ability and sociability of burn injured mice resembles the negative mood symptoms in PTSD. Burn mice showed extremely higher locomotion throughout the tests mimicking the arousal symptom in PTSD. Increased microgliosis astrocytosis and BDNF expression in the brain of burn mice may attribute to the neurobehavioral alterations. |
S0014488619302109 | Multiple sclerosis is an autoimmune disorder of the central nervous system characterized by locomotor impairments cognitive deficits affective disorders and chronic pain . Females are predominately affected by MS compared to males and develop motor symptoms earlier . However key symptoms affect all patients regardless of sex . Previous studies have shown that demyelination and axonal damage play key roles in symptom development but it is unclear why sex differences exist in MS onset and effective symptom treatment is still lacking . We here used a non pertussis toxin experimental autoimmune encephalomyelitis model in C57BL 6 mice to explore chronic symptoms and sex differences in CNS autoimmunity . We observed that like in humans female mice developed motor disease earlier than males . Further changes in pre and post synaptic protein expression levels were observed in a sexually dimorphic manner with an overall shift towards excitatory signaling . Our data suggest that this shift towards excitatory signaling is achieved through different mechanisms in males and females . Altogether our study helps to better understand sex specific disease mechanisms to ultimately develop better diagnostic and treatment tools . | nPTX EAE reflects some aspects female and male MS motor and sensory deficits. Behavioral deficits are seen in both female and male EAE. Macrophage mediated innate immune response is stronger in males. Synaptic protein expression are sexually dimorphic but favor excitatory signaling. |
S0014488619302110 | The excitatory neurotransmitter glutamate is essential in basal ganglia motor circuits and has long been thought to contribute to cell death and degeneration in Parkinson s disease . While previous research has shown a significant role of NMDA and AMPA receptors in both excitotoxicity and PD the third class of ionotropic glutamate receptors kainate receptors have been less well studied . Given the expression of kainate receptor subunits GluK1 GluK3 in key PD related brain regions it has been suggested that GluK1 GluK3 may contribute to excitotoxic cell loss . Therefore the neuroprotective potential of the kainate receptor antagonist UBP310 in animal models of PD was investigated in this study . Stereological quantification revealed administration of UBP310 significantly increased survival of dopaminergic and total neuron populations in the substantia nigra pars compacta in the acute MPTP mouse model of PD . In contrast UBP310 was unable to rescue MPTP induced loss of dopamine levels or dopamine transporter expression in the striatum . Furthermore deletion of GluK1 GluK2 or GluK3 had no effect on MPTP or UBP310 mediated effects across all measures . Interestingly UBP310 did not attenuate cell loss in the midbrain induced by intrastriatal 6 OHDA toxicity . These results indicate UBP310 provides neuroprotection in the midbrain against MPTP neurotoxicity that is not dependent on specific kainate receptor subunits . | UBP310 protects dopaminergic neurons from MPTP neurotoxicity. Single deletion of GluK1 GluK2 or GluK3 does not protect DA neurons from MPTP. Single deletion of GluK1 GluK2 or GluK3 does not alter the effects of UBP310. Suggests UBP310 does not mediate its effect via these receptor subunits alone. |
S0014488619302158 | Ischemic stroke is the most common type of cerebrovascular event and is responsible for approximately 85 of all strokes in Taiwan . Neurons contain high concentrations of polyamines which are prone to various pathological states in the brain and are perturbed after cerebral ischemia . Acrolein an unsaturated aldehyde has been suggested as the primary culprit of neuronal damage in stroke patients . However the mechanism by which acrolein induces neuronal damage during ischemic stroke is not clear . Urinary 3 hydroxypropyl mercapturic acid an acrolein glutathione metabolite plasma acrolein protein conjugates and plasma GSH levels were analyzed to correlate disease severity and prognosis of stroke patients compared with control subjects . A deregulated acrolein metabolism including significantly increased plasma Acr PC levels decreased urinary 3 HPMA levels and decreased plasma GSH levels was found in stroke patients compared to control subjects . We further observed that acrolein was produced during ischemia resulting in brain damage in Overall our current results demonstrate that acrolein is a culprit of neuronal damage through GSH depletion in stroke patients . The mechanism underlying the role of acrolein in stroke related neuronal damage occurs through SSAT induced polyamine oxidation by NF kB pathway activation . These results provide a novel mechanism of neurotoxicity in stroke patients aid in the development of neutralizing or preventive measures and further our understanding of neural protection . | A deregulated acrolein metabolism is found in stroke patients. Acrolein is produced resulting in brain damage in MCAO animal model. Acrolein occurs through SSAT induced polyamine oxidation by NF kB pathway. Acrolein elicits a vicious cycling of oxidative stress resulting in neurotoxicity. acetylcysteine prevents OGD induced neurotoxicity by scavenging acrolein. |
S001448861930216X | Respiratory motor neuron survival is critical for maintenance of adequate ventilation and airway clearance preventing dependence to mechanical ventilation and respiratory tract infections . Phrenic motor neurons are highly vulnerable in rodent models of motor neuron disease versus accessory inspiratory motor pools . Thus strategies that promote phrenic motor neuron survival when faced with disease and or toxic insults are needed to help preserve breathing ability airway defense and ventilator independence . Adenosine 2A receptors are emerging as a potential target to promote neuroprotection although their activation can have both beneficial and pathogenic effects . Since the role of A2A receptors in the phrenic motor neuron survival death is not known we tested the hypothesis that A2A receptor antagonism promotes phrenic motor neuron survival and preserves diaphragm function when faced with toxic neurodegenerative insults that lead to phrenic motor neuron death . We utilized a novel neurotoxic model of respiratory motor neuron death recently developed in our laboratory intrapleural injections of cholera toxin B subunit conjugated to the ribosomal toxin saporin . We demonstrate that intrapleural CtB Saporin causes 1 profound phrenic motor neuron death 2 7 fold increase in phrenic motor neuron A2A receptor expression prior to cell death and 3 diaphragm muscle paralysis . The A2A receptor antagonist istradefylline given after CtB Saporin 1 reduced phrenic motor neuron death and 2 preserved diaphragm EMG activity . Thus A2A receptors contribute to neurotoxic phrenic motor neuron death an effect mitigated by A2A receptor antagonism . | Intrapleural cholera toxin beta subunit CtB conjugated saporin administration causes toxic phrenic motor neuron death. Intrapleural CtB Saporin causes upregulation of neuronal A2A receptors prior to phrenic motor neuron death. A2A receptor inhibition protects phrenic motor neurons from death and preserves diaphragm activity. |
S0014488619302171 | The adult mammalian central nervous system rarely recovers from injury . Myelin fragments contain axonal growth inhibitors that limit axonal regeneration thus playing a major role in determining neural recovery . Nogo receptor 1 and its ligands are among the inhibitors that limit axonal regeneration . It has been previously shown that the endogenous protein lateral olfactory tract usher substance antagonizes NgR1 mediated signaling and accelerates neuronal plasticity after spinal cord injury and cerebral ischemia in mice . However it remained unclear whether LOTUS mediated reorganization of descending motor pathways in the adult brain is physiologically functional and contributes to functional recovery . Here we generated LOTUS overexpressing transgenic rats to investigate the role of LOTUS in neuronal function after damage . After unilateral pyramidotomy motor function in LOTUS Tg rats recovered significantly compared to that in wild type animals . In a retrograde tracing study labeled axons spanning from the impaired side of the cervical spinal cord to the unlesioned hemisphere of the red nucleus and sensorimotor cortex were increased in LOTUS Tg rats . Anterograde tracing from the unlesioned cortex also revealed enhanced ipsilateral connectivity to the impaired side of the cervical spinal cord in LOTUS Tg rats . Moreover electrophysiological analysis showed that contralesional cortex stimulation significantly increased ipsilateral forelimb movement in LOTUS Tg rats which was consistent with the histological findings . According to these data LOTUS overexpression accelerates ipsilateral projection from the unlesioned cortex and promotes functional recovery after unilateral pyramidotomy . LOTUS could be a future therapeutic option for CNS injury . | LOTUS Tg rats allowed the study of endogenous NgR1 antagonist function. LOTUS was overexpressed in the cervical spinal cord after unilateral pyramidotomy. LOTUS Tg rats had faster functional improvement after unilateral pyramidotomy. LOTUS promoted neural plasticity and unlesioned cortexdenervated side connection. LOTUS promoted functional improvement after central nervous system injury. |
S0014488619302201 | Targeting interhemispheric inhibition using brain stimulation has shown potential for enhancing stroke recovery . Following stroke increased inhibition originating from the contralesional hemisphere impairs motor activation in ipsilesional areas . We have previously reported that low intensity electrical theta burst stimulation applied to an implanted electrode in the contralesional rat motor cortex reduces interhemispheric inhibition and improves functional recovery when commenced three days after cortical injury . Here we apply this approach at more clinically relevant later time points and measure recovery from photothrombotic stroke following three weeks of low intensity intermittent TBS continuous TBS or sham stimulation applied to the contralesional motor cortex . Interhemispheric inhibition and cellular excitability were measured in the same rats from single pyramidal neurons in the peri infarct area using | Three weeks of contralesional electrical intermittent theta burst stimulation from 10 days post stroke enhances recovery in rats. Functional recovery following contralesional stimulation positively correlates with excitability of the ipsilesional cortex. Interhemispheric inhibition negatively correlates with ipsilesional excitability but not with functional recovery. |
S0014488619302213 | Following injury sensory axons locally translate mRNAs that encode proteins needed for the response to injury locally and through retrograde signaling and for regeneration . In this study we addressed the mechanism and role of axotomy induced intra axonal translation of the ER chaperone Calreticulin . In vivo peripheral nerve injury increased Calreticulin levels in sensory axons . Using an in vitro model system of sensory neurons amenable to mechanistic dissection we provide evidence that axotomy induces local translation of Calreticulin through PERK mediated phosphorylation of eIF2 by a mechanism that requires both 5 and 3UTRs elements in Calreticulin mRNA . ShRNA mediated depletion of Calreticulin or inhibition of PERK signaling increased axon retraction following axotomy . In contrast expression of axonally targeted but not somatically restricted Calreticulin mRNA decreased retraction and promoted axon regeneration following axotomy in vitro . Collectively these data indicate that the intra axonal translation of Calreticulin in response to axotomy serves to minimize the ensuing retraction and overexpression of axonally targeted Calreticulin mRNA promotes axon regeneration . | Axotomy increase axonal Calreticulin translation in the PNS. Injury induced PERK dependent Phospho eIF2 triggers axonal Calreticulin translation. Control of Calreticulin translation in axons requires both 5 and 3UTR mRNA motifs. Calreticulin translation in cut axons reduces retraction and facilitates regeneration. |
S0014488619302225 | During mammalian embryonic development sensory and motor axons interact as an integral part of the pathfinding process . During regeneration however little is known of their interactions with one another . It is thus possible that sensory axons might influence motor axon regeneration in ways not currently appreciated . To explore this possibility we have developed an organotypic model of post natal nerve regeneration in which sensory and motor axons are color coded by modality . Motor axons that express yellow fluorescent protein and sensory axons that express red fluorescent protein are blended within a three dimensional segment of peripheral nerve . This nerve is then transected allowing axons to interact with one another as they grow out on a collagen laminin gel that is initially devoid of directional cues . Within hours it is apparent that sensory axons extend more rapidly than motor axons and precede them during the early stages of regeneration the opposite of their developmental order . Motor axons thus enter an environment already populated with sensory axons and they adhere to these axons throughout most of their course . As a result motor axon growth is reduced dramatically . Physical delay of sensory regeneration allowing motor axons to grow ahead restores normal motor growth direct axonal interactions on the gel rather than some other aspect of the model are thus responsible for motor inhibition . Potential mechanisms for this inhibition are explored by electroporating siRNA to the neural cell adhesion molecule and the L1 adhesion molecule into dorsal root ganglia to block expression of these molecules by regenerating sensory axons . Although neither maneuver improved motor regeneration the results were consistent with early receptor mediated signaling among axons rather than physical adhesion as the mechanism of motor inhibition in this model . | The interaction of regenerating color coded sensory and motor axons is studied in a new. model of post natal mammalian mixed nerve regeneration. Sensory axons regenerate more rapidly than motor axons. Regenerating motor axons adhere to sensory axons throughout most of their course. Interaction with sensory axons inhibits motor axon regeneration. Delay of sensory axon regeneration restores normal motor regeneration |
S0014488619302237 | Nerve graft reconstruction of gap defects may result in poor clinical outcomes particularly with long regeneration distances . Electrical stimulation of nerves may improve outcomes in such patients . A single session of ES at 20Hz for 1h significantly enhances axon regeneration in animals and human subjects after nerve crush or nerve transection and repair . The objectives of this study were to evaluate if ES enhances axon regeneration through nerve grafts and if there is added benefit of a second delayed session of ES on axon regeneration as compared to a single session only of ES . In female rats a gap defect was created in the hindlimb common peroneal nerve and immediately reconstructed with a 10mm nerve autograft or a 20mm nerve autograft . In Experiment 1 rats were randomized to 1h of CP nerve ES or sham stimulation . In Experiment 2 rats were randomized to control single ES or serial ES which consisted of an initial 1h session of either ES or sham stimulation of the CP nerve followed by a second 1h session of ES or sham stimulation of the CP nerve 4weeks later . In both experiments after a 6week period of nerve regeneration CP neurons that had regenerated axons distal to the autograft were retrograde labelled for enumeration and the CP nerve distal to the autograft was harvested for histomorphometry . In Experiment 1 rats that received CP nerve ES had statistically significantly more motor | A single 1h session of 20Hz direct nerve electrical stimulation enhances axon regeneration through nerve autografts. Direct nerve electrical stimulation increases axonal branching through nerve autografts. A second delayed 1h session of 20Hz direct nerve electrical stimulation does not further enhance axon regeneration through nerve autografts. |
S0014488619302249 | Obstructive sleep apnea a chronic sleep disorder characterized by repetitive reduction or cessation of airflow during sleep is widely prevalent and is associated with adverse neurocognitive sequelae including increased risk of Alzheimer s disease . In humans OSA is more common in elderly males . OSA is characterized by sleep fragmentation and chronic intermittent hypoxia and recent epidemiological studies point to CIH as the best predictor of neurocognitive sequelae associated with OSA . The sex and age specific effects of OSA associated CIH on specific cell populations such as aminobutyric acid ergic neurons in the hippocampus and the medial prefrontal cortex regions important for cognitive function remain largely unknown . The present study examined the effect of 35days of either moderate or severe CIH on GABAergic neurons in the mPFC and hippocampus of young and aged male and female mice as well as post accelerated ovarian failure female mice . In the mPFC and hippocampus the number of GABA labeled neurons increased in aged and young severe CIH males compared to controls but not in young moderate CIH males . This change was not representative of the individual GABAergic cell subpopulations as the number of parvalbumin labeled neurons decreased while the number of somatostatin labeled neurons increased in the hippocampus of severe CIH young males only . In all female groups the number of GABA labeled cells was not different between CIH and controls . However in the mPFC CIH increased the number of parvalbumin labeled neurons in young females and the number of somatostatin labeled cells in AOF females but decreased the number of somatostatin labeled cells in aged females . In the hippocampus CIH decreased the number of somatostatin labeled neurons in young females . CIH decreased the density of vesicular GABA transporter in the mPFC of AOF females only . These findings suggest sex specific changes in GABAergic neurons in the hippocampus and mPFC with males showing an increase of this cell population as compared to their female counterparts following CIH . Age at exposure and severity of CIH also differentially affect the GABAergic cell population in mice . | Age and hypoxia severity increase neuronal GABA labeling in male mice. Female mice show no changes in GABA labeling following chronic intermittent hypoxia. In young hypoxic mice DG somatostatin increased in males and decreased in females. Vesicular GABA transporter was affected in accelerated ovarian failure females only. These sex differences might have important implications for clinical OSA patients. |
S0014488619302250 | HIV associated neurocognitive disorders continue to persist despite effective control of viral replication . Although the mechanisms underlying HAND are poorly understood recent attention has focused on altered neuronal population activity as a correlate of impaired cognition . However while alterations in neuronal population activity in the gamma frequency range are noted in the setting of HAND the underlying mechanisms for these changes is unclear . Perineuronal nets are a specialized extracellular matrix that surrounds a subset of inhibitory neurons important to the expression of neuronal oscillatory activity . In the present study we observe that levels of PNN degrading matrix metalloproteinases are elevated in HIV infected post mortem human brain tissue . Furthermore analysis of two PNN components aggrecan and brevican reveals increased proteolysis in HIV infected brains . In addition local field potential recordings from | Altered brain oscillations have been previously reported in HIV patients. Increased MMP expression and PNN proteolysis is observed in HIV brain tissue. PNN degradation in murine hippocampal slices results in increased gamma power. Aberrant PNN proteolysis may underlie altered brain oscillations in HIV patients. |
S0014488619302274 | Migraine is a complex brain disorder that involves abnormal activation of the trigeminocervical complex . Since an increase of oxytocin concentration has been found in cerebrospinal fluid in migrainous patients and intranasal oxytocin seems to relieve migrainous pain some studies suggest that the hypothalamic neuropeptide oxytocin may play a role in migraine pathophysiology . However it remains unknown whether oxytocin can interact with the trigeminovascular system at TCC level . The present study was designed to test the above hypothesis in a well established electrophysiological model of migraine . Using anesthetized rats we evaluated the effect of oxytocin on TCC neuronal activity in response to dural nociceptive trigeminovascular activation . We found that spinal oxytocin significantly reduced TCC neuronal firing evoked by meningeal electrical stimulation . Furthermore pretreatment with L 368 899 abolished the oxytocin induced inhibition of trigeminovascular neuronal responses . This study provides the first direct evidence that oxytocin probably by OTR activation at TCC level inhibited dural nociceptive evoked action potential in this complex . Thus targeting OTR at TCC could represent a new avenue to treat migraine . | The trigeminocervical complex TCC is involved in migraine and dural nociception. Oxytocin at TCC inhibits the dural evoked nociception. Blockade of oxytocin receptors OTR at TCC abolished the OXT induced antinociception. Relevance of oxytocinergic neurotransmission modulating migraine is suggested. |
S0014488619302298 | Phosphatase and tensin homolog induced kinase 1 is involved in mitochondrial quality control which is essential for maintaining energy production and minimizing oxidative damage from dysfunctional depolarized mitochondria . Pink1 mutations are the second most common cause of autosomal recessive Parkinson s disease . In addition to characteristic motor impairments PD patients also commonly exhibit cognitive impairments . As the hippocampus plays a prominent role in cognition we tested if loss of Pink1 in mice influences learning and memory . While wild type mice were able to perform a contextual discrimination task age matched | Hippocampal mitochondrial length is not affected by loss of Pink1. mice have reduced hippocampal tyrosine hydroxylase immunoreactivity. mice are impaired in hippocampus dependent tasks compared to matched WT mice. Cognition in. mice is improved by treatment with a dopamine D1 agonist |
S0014488619302304 | Chitinase 3 like 1 plays a major role in the pathogenesis of inflammatory diseases . We investigated the effect of Chi3L1 knockout on stroke development . Ischemia reperfusion was induced by middle cerebral artery occlusion in Chi3L1 knockout and wildtype mice . Significantly increased infarct volume and decreased neurological deficit scores at 24h after ischemia reperfusion were found in Chi3L1 knockout mice compared to wildtype mice . Moreover ischemic neuronal cell death was increased in Chi3L1 knockout mice through increased oxidative stress and release of IL 6 and IL 1 but IL 10 and IL 4 were reduced . Furthermore expression of inflammation related proteins was significantly increased in Chi3L1 knockout mice compared to wildtype . In microglia isolated from MCAO injured Chi3L1 knockout mice expression of M1 markers was increased and M2 markers was decreased . In BV 2 cells knockdown of Chi3L1 increased TNF and INF induced expression of iNOS COX 2 and Iba 1 but decreased the expression of Arg1 MRC1 and IL 4 receptor alpha . Expression of IL 4R an important factor of M2 polarization and its downstream signals p JAK1 p JAK3 and p STAT6 was much reduced in the knockout mice . Additionally in BV 2 cells knockdown of Chi3L1 by siRNA Chi3L1 decreased rhTNF and INF induced expression of IL 4R p JAK1 p JAK3 and p STAT6 . Furthermore treatment with AS1517499 abolished Chi3L1 knockdown induced reduced IL 4R and Arg1 but not CD86 expression . Our results indicate that deletion of Chi3L1 accelerates stroke development through enhancement of neuroinflammation by markedly decreasing STAT6 dependent M2 macrophage polarization . | Chi3L1 is important for IL 4R expression and phosphorylation of STAT6 affecting micorglial M2 polarization. Knockdown of Chi3L1 decrease IL 4R p JAK1 p JAK3 and p STAT6 expression level which blocking microglial M2 polarization. Absence of Chi3L1 accelerates stroke development through STAT6 dependent M2 microglia inactivation. |
S0014488619302316 | Spinal cord injury can have profound effects on the autonomic and cardiovascular systems notably with injuries above high thoracic levels that result in the development of autonomic dysreflexia characterized by volatile hypertension in response to exaggerated sympathetic reflexes triggered by afferent stimulation below the injury level . Pathophysiological changes associated with the development of AD include sprouting of both nociceptive afferents and ascending propriospinal relay neurons below the injury as well as dynamic changes in synaptic inputs onto sympathetic preganglionic neurons . However it remains uncertain whether synapse formation between sprouted c fibers and propriospinal neurons contributes to the development of exaggerated sympathetic reflexes produced during AD . We previously reported that once daily treatment with the anti epileptic and neuropathic pain medication gabapentin at low dosage mitigates experimentally induced AD soon after injections likely by impeding glutamatergic signaling . Since much higher doses of GBP are reported to block the formation of excitatory synapses we hypothesized that continuous high dosage GBP treatment after SCI might prevent the formation of aforementioned aberrant synapses and accordingly reduce the incidence and severity of AD . Adult female rats implanted with aortic telemetry probes for hemodynamic monitoring underwent T4 transection SCI and immediately received 100mg kg of GBP and then every six hours for 4 weeks after injury . We assessed daily body weight mean arterial pressure heart rate frequency of spontaneous AD and hemodynamic changes during colorectal distension to establish whether high dose GBP treatment prophylactically mitigates both AD and associated aberrant synaptic plasticity . This regimen significantly reduced both the absolute blood pressure reached during experimentally induced AD and the time required to return to baseline afterwards . Conversely GBP prevented return to pre injury body weights and paradoxically increased the frequency of spontaneously occurring AD . While there were significant decreases in the densities of excitatory and inhibitory pre synaptic markers in the lumbosacral dorsal horn following injury alone they were unaltered by continuous GBP treatment . This indicates distinct mechanisms of action for acute GBP to mitigate induced AD whereas chronic GBP increases non induced AD frequencies . While high dose prophylactic GBP is not recommended to treat AD acute low dose GBP may hold therapeutic value to mitigate evoked AD notably during iatrogenic procedures under controlled clinical conditions . | Chronic high dose GBP after SCI reduces AD evoked by noxious colorectal stimulation. High dose GBP impairs weight gain promotes splenomegaly and increase sAD events. Reduced synaptic densities after SCI are unaltered by high dose GBP treatment. GBP alters induced AD and sAD events distinctly perhaps acting on vasculature. Low or high dose acute GBP may be relevant in controlled settings to reduce AD. |
S001448861930233X | Muscular dystrophies are a group of genetic muscle disorders that cause progressive muscle weakness and degeneration . Within this group Duchenne muscular dystrophy is the most common and one of the most severe . DMD is an X chromosome linked disease that occurs to 1 in 3500 to 1 in 5000 boys . The cause of DMD is a mutation in the dystrophin gene whose encoded protein provides both structural support and cell signaling capabilities . So far there are very limited therapeutic options available and there is no cure for this disease . In this review we discuss the existing cell therapy research especially stem cell based which utilize myoblasts satellite cells bone marrow cells mesoangioblasts and CD133 cells . Finally we focus on human pluripotent stem cells which hold great potential in treating DMD . hPSCs can be used for autologous transplantation after being specified to a myogenic lineage . Over the last few years there has been a rapid development of isolation as well as differentiation techniques in order to achieve effective transplantation results of myogenic cells specified from hPSCs . In this review we summarize the current methods of hPSCs myogenic commitment differentiation and describe the current status of hPSC derived myogenic cell transplantation . | Myogenic progenitor cells could provide a source for cell therapy for DMD to regenerate and replace the diseased tissue. An orchestration of signaling molecules directing the lineage determination sets the basis for PSC differentiation. There is a need to develop more cell therapy options e.g iPSC for DMD due to limited success of current ones. The review describes the most recent studies of hiPSC muscle lineage specification and the potential of their application |
S0014488619302341 | Neonatal encephalopathy frequently results from hypoxia ischemia or inflammation in preterm or term neonates . Neuropathology depends on cerebral development at insult time but the poor correlation of neuromotor cognitive and behavioral disabilities in infancy with initial imaging and clinical records precludes early prognosis . The RiceVannucci HI procedure was applied to wild type and tissue plasminogen activator knockout mice as surrogates for human preterm mice or human term mice . Acute and delayed T2 magnetic resonance imaging signals and cognitive deficits in adulthood were investigated in the same animals . Early vascular tPA and matrix metalloproteinase 9 activities bloodbrain barrier permeability to water or IgG and microglial activation were assessed separately . | Neonatal mice aged 5 or 10days exposed to HI exhibit different T2 MRI profiles. White matter has specific MMP 9 dependent vascular vulnerability in 5 day old mice. 5 day old mice had white matter T2 MRI hypersignals and social interaction deficits. 10 day old mice had coincidental retrosplenial damage and spatial memory deficits. tPA KO prevents BBB leakage microglial activation depending on age and structures |
S0014488619302353 | Vitronectin is a blood protein produced mainly by the liver . We show that VTN leaks from the bloodstream into the injury site and neighboring subventricular zone following ischemic stroke in adult mice . MCAO is known to increase neurogenesis after stroke . VTN inhibits this response in females but not in males as shown by 70 more stroke induced SVZ neurogenesis in female VTN mice at 14 d. In female VTN mice stroke induced expression of interleukin 6 at 24h was reduced in the SVZ . The closely related leukemia inhibitory factor or pro neurogenic ciliary neurotrophic factor were not affected . The female specific effect of VTN on IL 6 expression was not due to sex hormones as shown by ovariectomy and castration . IL 6 injection next to the SVZ reversed the MCAO induced increase in neurogenesis seen in VTN mice . Our in vitro and vivo data suggest that plasma VTN activates focal adhesion kinase in the SVZ following MCAO which reduces IL 6 expression in astrocytes but increases it in other cells such as microglia macrophages . Inducible conditional astrocytic FAK deletion increased MCAO induced IL 6 expression in females at 24h and blocked MCAO induced neurogenesis at 14d confirming a key detrimental role of IL 6 . Collectively these data suggest that leakage of VTN into the SVZ reduces the neurogenic response to stroke in female mice by promoting IL 6 expression . Reducing VTN or VTN signaling may be an approach to promote neurogenesis for neuroprotection and cell replacement after stroke in females . | Vitronectin VTN leaks from blood into the subventricular zone SVZ of adult mice after ischemic stroke. VTN inhibits stroke induced SVZ neurogenesis in females but not males by promoting acute expression of SVZ IL 6. The female specific VTN induced IL 6 was through activation of FAK signaling but not due to gonadal hormones. Astrocytic FAK plays a role in repressing stroke induced IL 6 in females only. VTN or VTN signaling may be a good targets for promoting neurogenesis for neuroprotection and cell replacement in females. |
S0014488619302365 | Serotonin axons in the adult rodent brain can regrow and recover their function following several forms of injury including controlled cortical impact a neocortical stab wound or systemic amphetamine toxicity . To assess whether this capacity for regrowth is unique to serotonergic fibers we used CCI and stab injury models to assess whether fibers from other neuromodulatory systems can also regrow following injury . Using tyrosine hydoxylase immunohistochemistry we measured the density of catecholaminergic axons before and at various time points after injury . One week after CCI injury we observed a pronounced loss across cortical layers of TH axons posterior to the site of injury . One month after CCI injury the same was true of TH axons both anterior and posterior to the site of injury . This loss was followed by significant recovery of TH fiber density across cortical layers both anterior and posterior to the site of injury measured three months after injury . TH axon loss and recovery over weeks to months was also observed throughout cortical layers using the stab injury model . Double label immunohistochemistry revealed that nearly all TH axons in neocortical layer 1 2 are also dopamine beta hyroxylase while TH axons in layer 5 are a mixture of DBH and dopamine transporter types . This suggests that noradrenergic axons can regrow following CCI or stab injury in the adult mouse neocortex and leaves open the question of whether dopaminergic axons can do the same . | We measured catecholaminergic axon density using TH immunohistochemistry following two forms of brain injury. Controlled cortical impact and stab injuries caused extensive damage to catecholamine axons in the neocortex of adult mice. Following both types of injury axon density slowly returned to control values over many weeks. These findings suggest that monaminergic axons have an unusual capacity for regrowth following injury in the adult brain. |
S0014488619302377 | Non mammalian models of CIPN remain relatively sparse but the knowledge gained from the few published studies suggest that these species have great potential to serve as a discovery platform for new pathways and underlying genetic mechanisms of CIPN . These models permit large scale genetic and pharmacological screening and they are highly suitable for | and zebrafish as chemotherapy induced neurotoxicity models. imaging revealed new CIPN mechanisms with conserved functions in mammals. NMNAT DLK and MORN are major players in the control of paclitaxel induced axon degeneration. ROS and altered microtubule function are aberrant in paclitaxel induced peripheral neuropathy. Epidermal damage contributes to paclitaxel neurotoxicity through activation of MMP 13. |
S0014488619302389 | Neurotrophic factors as candidates for ALS therapeutics have previously been studied in the context of attempts to slow disease progression . For a variety of reasons clinical trials of neurotrophic factors have failed to show efficacy in ALS patients . Previous studies in Parkinson s Disease models have shown promise with the use of recombinant adeno associated virus serotype 2 neurturin providing neuroprotection and behavioral improvements in preclinical models which subsequently resulted in several clinical studies in patients with PD . Given that this neurotrophic compound has not been studied in the context of ALS we conducted a study of AAV2 NRTN to assess the preclinical safety tolerability biodistribution and efficacy of this compound in an ALS mouse model . SOD1 | AAV2 NRTN injected into spinal cords of ALS mice provides long term expression of NRTN in motor neurons. AAV2 NRTN delivery results in a dose dependent neuroprotection of motor neurons and neuromuscular junctions. The neuroprotective effects correlate with a slowing of grip strength decline in this ALS model. The history of AAV2 NRTN in previous clinical trials suggests this approach could be an ALS treatment strategy. |
S0014488619302390 | Dramatic impairment of gastrointestinal function accompanies high thoracic spinal cord injury . The vagus nerve contains mechano and chemosensory fibers as well as the motor fibers necessary for the central nervous system control of GI reflexes . Cell bodies for the vagal afferent fibers are located within the nodose gangla and the majority of vagal afferent axons are unmyelinated C fibers that are sensitive to capsaicin through activation of transient receptor potential vanilloid 1 channels . Vagal afferent fibers also express receptors for GI hormones including cholecystokinin . Previously T3 SCI provokes a transient GI inflammatory response as well as a reduction of both gastric emptying and centrally mediated vagal responses to GI peptides including CCK . TRPV1 channels and CCK A receptors expressed in vagal afferents are upregulated in models of visceral inflammation . The present study investigated whether T3 SCI attenuates peripheral vagal afferent sensitivity through plasticity of TRPV1 and CCK receptors . | Upper thoracic SCI impairs mechanosensitivity of gastric vagal afferent fibers. Vagal sensory cell soma show post injury CCK A receptor and TRPV1 channel plasticity. Acute gastric vagal afferent sensitivity to CCK is diminished following SCI. Gastric vagal afferents have elevated sensitivity to the TRPV1 agonist capsaicin. Chronic SCI rats display a bimodal recovery of sensitivity to CCK. |
S0014488619302419 | Given the essential role of the blood brain barrier in the central nervous system cumulative investigations have been performed to elucidate how modulation of BBB structural and functional integrity affects the pathogenesis of CNS diseases such as stroke traumatic brain injuries dementia and cerebral infection . Recent studies have demonstrated that microRNAs contribute to the maintenance of the BBB and thereby mediate CNS homeostasis . This review summarizes emerging studies that demonstrate cerebral miRNAs regulate BBB function in CNS disorders emphasizing the direct role of miRNAs in BBB molecular composition . Evidence presented in this review will encourage a deeper understanding of the mechanisms by which miRNAs regulate BBB function and facilitate the development of new miRNAs based therapies in patients with CNS diseases . | MiRNAs play a crucial role in the regulation of BBB structure and function. MiRNAs directly regulate the expression of junctional proteins in CNS diseases. MiRNAs mediate BBB structure and function. multiple mechanisms in CNS diseases. |
S0014488619302420 | Currently molecular electrophysiological and structural studies delineate several neural subtypes in the hippocampus . However the precise developmental mechanisms that lead to this diversity are still unknown . Here we show that alterations in a concrete hippocampal neuronal subpopulation during development specifically affect hippocampal dependent spatial memory . We observed that the genetic deletion of the transcription factor Helios in mice which is specifically expressed in developing hippocampal calbindin positive CA1 pyramidal neurons induces adult alterations affecting spatial memory . In the same mice CA3 CA1 synaptic plasticity and spine density and morphology in adult CB CA1 PNs were severely compromised . RNAseq experiments in developing hippocampus identified an aberrant increase on the Visinin like protein 1 expression in the hippocampi devoid of Helios . This aberrant increase on VSNL1 levels was localized in the CB CA1 PNs . Normalization of VSNL1 levels in CB CA1 PNs devoid of Helios rescued their spine loss | Helios is a transcription factor that is specifically expressed in calbindin positive CA1 pyramidal neurons during development. Adult mice devoid of Helios display a specific decrease in spine density in calbindin positive CA1 pyramidal neurons an impaired spatial learning and a decreased CA3 CA1 long term potentiation. VSNL1 is finely regulated by Helios during development and we show. evidences suggesting that VSNL1 occluded expression could be the responsible for the spine loss observed in mice devoid of Helios. |
S0014488619302432 | Central post stroke pain can occur after stroke in the somatosensory pathway that includes the posterolateral region of the thalamus . Tactile allodynia in which innocuous tactile stimuli are perceived as painful is common in patients with CPSP . Previous brain imaging studies have reported plastic changes in brain activity in patients with tactile allodynia after stroke but a causal relationship between such changes and the symptoms has not been established . We recently developed a non human primate model of CPSP based on thalamic lesions in which the animals show behavioral changes consistent with the occurrence of tactile allodynia . Here we performed functional magnetic resonance imaging under propofol anesthesia to investigate the changes in brain activation associated with the allodynia in this CPSP model . Before the lesion innocuous tactile stimuli significantly activated the contralateral sensorimotor cortex . When behavioral changes were observed after the thalamic lesion equivalent stimuli significantly activated pain related brain areas including the posterior insular cortex secondary somatosensory cortex anterior cingulate cortex and amygdala . Moreover when either PIC SII or ACC was pharmacologically inactivated the signs of tactile allodynia were dampened . Our results show that increased cortical activity plays a role in CPSP induced allodynia . | Change in brain activation in CPSP monkey model was investigated. fMRI showed activation of pain related brain areas including ACC and PIC SII. Allodynia was dampened by pharmacological inactivation of ACC or PIC SII. These findings suggest that CPSP is mediated by the increased cortical activity. |
S0014488619302444 | Regeneration after spinal cord injury is a goal of many studies . Although the most obvious target is to recover motor function restoration of sensation can also improve the quality of life after spinal cord injury . For many patients recovery of sensation in the perineal and genital area is a high priority . Currently there is no experimental test in rodents for measuring changes in sensation in the perineal and genital area after spinal cord injury . The aim of our study was to develop a behavioural test for measuring the sensitivity of the perineal and genital area in rats . We have modified the tape removal test used routinely to test sensorimotor deficits after stroke and spinal cord injury to test the perineal area with several variations . A small piece of tape approximately 1cm | The modified tape removal test is suitable for testing the perineal area sensitivity. Detects deficits in the sensation after spinal cord injury for at least 3weeks. Correlates with the size of the lesion. Suitable for testing treatments for sensory restoration in the genital region. |
S0014488619302572 | Parkinson s disease is a progressive and chronic neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta and affects multiple neurotransmission systems such as hypocretin orexin release and can lead to cognitive and memory deficits . The HO neurons located in lateral hypothalamus perifornical area are involved with consolidation and memory processes . Here we verified the involvement of HO deficit in learning and memory process in an animal model of PD induced by bilateral intra striatal injections of 6 hydroxydopamine . The present study performed a working memory test by object recognition task and spatial memory test using the Morris water maze in control and PD induced animals after depletion of HO neurons . In addition our results indicate that HO system in degenerative disorders such as PD may modulate the declarative and spatial memory . A significant reduction of HO neurons in the LH PeF and HO degeneration process in the hippocampus were noticed . Our data suggest that the HO system degeneration could be associated to memory dysfunction in PD . | PD animals present reduction of HO neurons. HO inputs to CA1 and DG are degenerated in PD. HO reduction correlates to impaired spatial and declarative memory in control and PD animals. |
S0014488619302584 | Restless legs syndrome is a nocturnal neurological disorder affecting up to 10 of the population . It is characterized by an urge to move and uncomfortable sensations in the legs which can be relieved by movements . Mutations in | knockout KO mice had increased excitability in primary sensory cortex. KO mice had decreased cortical thickness in part of the S1 and M1. KO mice showed increased corticostriatal PPF and motor deficits. Cerebral cortex specific. KO mice. cKO had RLS like phenotypes. cKO showed decreased thickness in part of the S1 and M1 and motor deficits. |
S0014488619302602 | A synthetic monomeric peptide triple receptor agonist termed Triagonist that incorporates glucagon like peptide 1 glucose dependent insulinotropic polypeptide and glucagon actions was previously developed to improve upon metabolic and glucose regulatory benefits of single and dual receptor agonists in rodent models of diet induced obesity and type 2 diabetes . In the current study the neurotrophic and neuroprotective actions of this Triagonist were probed in cellular and mouse models of mild traumatic brain injury a prevalent cause of neurodegeneration in both the young and elderly . Triagonist dose and time dependently elevated cyclic AMP levels in cultured human SH SY5Y neuronal cells and induced neurotrophic and neuroprotective actions mitigating oxidative stress and glutamate excitotoxicity . These actions were inhibited only by the co administration of antagonists for all three receptor types indicating the balanced co involvement of GLP 1 GIP and Gcg receptors . To evaluate physiological relevance a clinically translatable dose of Triagonist was administered subcutaneously once daily for 7days to mice following a 30g weight drop close head injury . Triagonist fully mitigated mTBI induced visual and spatial memory deficits evaluated at 7 and 30days post injury . These results establish Triagonist as a novel neurotrophic protective agent worthy of further evaluation as a TBI treatment strategy . | The GLP 1 GIP Gcg Triagonist is neurotrophic in neuronal SH SY5Y cultures. Triagonist is neuroprotective against oxidative stress and glutamate excitotoxicity. Triagonist neurotrophic protective actions are balanced across receptors. Triagonist reduces microglial cell inflammation. Triagonist mitigates mild TBI induced visual and spatial memory impairments. |
S0014488619302626 | We recently identified excessive cerebral kallikrein 8 mRNA and protein levels at incipient stages of Alzheimer s disease in AD patients and TgCRND8 mice . Additionally we showed that antibody mediated KLK8 inhibition exerts therapeutic effects on AD along with enhancing neuroplasticity resulting in improved spatial memory in mice . Mounting evidence further substantiates an important role of the protease KLK8 in neuroplasticity . In the present study we sought to gain new mechanistic insights in the interplay between KLK8 neuroplasticity and tau phosphorylation in the context of AD . We here demonstrate that KLK8 inhibition increased the number of hippocampal Ki 67 and doublecortin positive proliferative neuronal progenitor cells in transgenic mice whereas the same action in wildtypes had no effect . In line with these results KLK8 inhibition reduced the levels of its pro proliferative interaction partners KLK6 and protease activated receptor 2 only in wildtypes while the levels of its proliferation supporting substrate neuregulin 1 and the non complexed form of its complexing partner phosphatidylethanolamine binding protein 1 were enhanced in both genotypes . Concomitant incubation of beta amyloid producing primary neurons with KLK8 and its inhibitory antibody increased neurite complexity and soma size . KLK8 inhibition in SH SY5Y cells or in primary neurons increased levels of the neuroplasticity supporting KLK8 substrate ephrin receptor B2 and total tau while decreasing the relative amount of phospho tau in relation to total tau . KLK8 blockade further enhanced cell proliferation in SH SY5Y cells . Additional co incubation with an inhibitory anti EPHB2 antibody decreased total tau levels and neurite complexity and increased the ratio of phospho tau total tau underlining the key role of EPHB2 on this plastic change . In a reverse in vitro approach KLK8 induction reduced EPHB2 and total tau and increased the ratio of phospho tau total tau leading to impaired proliferation and neuronal differentiation . These results underline the therapeutic potential of KLK8 inhibition by counteracting plasticity deficits in AD affected brain . | KLK8 inhibition increases the number of neuronal progenitor cells in transgenic mice. KLK8 inhibition promotes and KLK8 activation hampers SH SY5Y cell proliferation. KLK8 inhibition increases neuroplasticity promoting interaction partners in vivo. KLK8 inhibition increases and KLK8 induction reduces neurite complexity in vitro. KLK8 inhibition increases and EPHB2 inhibition reduces total tau. |
S0014488619302638 | Traumatic brain injury is a leading cause of death and disability in modern societies . Diffuse axonal and vascular injury are nearly universal consequences of mechanical energy impacting the head and contribute to disability throughout the injury severity spectrum . CHIMERA is a non surgical impact acceleration model of rodent TBI that reliably produces diffuse axonal injury characterized by white matter gliosis and axonal damage . At impact energies up to 0.7 joules which result in mild TBI in mice CHIMERA does not produce detectable vascular or grey matter injury . This study was designed to expand CHIMERA s capacity to induce more severe injuries including vascular damage and grey matter gliosis . This was made possible by designing a physical interface positioned between the piston and animal s head to allow higher impact energies to be transmitted to the head without causing skull fracture . Here we assessed interface assisted single CHIMERA TBI at 2.5 joules in wild type mice using a study design that spanned 6h60d time points . Injured animals displayed robust acute neurological deficits elevated plasma total tau and neurofilament light levels transiently increased proinflammatory cytokines in brain tissue blood brain barrier leakage and microstructural vascular abnormalities and grey matter microgliosis . Memory deficits were evident at 30d and resolved by 60d . Intriguingly white matter injury was not remarkable at acute time points but evolved over time with white matter gliosis being most extensive at 60d . Interface assisted CHIMERA thus enables experimental modeling of distinct endophenotypes of TBI that include acute vascular and grey matter injury in addition to chronic evolution of white matter damage similar to the natural history of human TBI . | We expanded the capacity of the mouse CHIMERA model to induce more severe injuries. Interface assisted single CHIMERA TBI induced acute neurological deficits in mice. Plasma total tau and neurofilament light levels were elevated after a single injury. Acute microstructural vascular abnormalities and grey matter microgliosis were observed. Memory deficits were evident at 30days post injury and resolved by day 60. |
S001448861930264X | Previous studies have shown that simvastatin has neuroprotective effects in a neonatal model of hypoxia ischemia induced brain injury when administered before but not after HI pointing to the preconditioning like effects of the statin . The present study aimed to gain more insight into the PC like effect of Sim by studying the role of autophagy and its modulation by mTOR and SIRT1 in neuroprotection . Sim potentiated the autophagy response induced by neonatal HI as shown by the increased expression of both microtubule associated protein 1 light chain 3 and beclin 1 increased monodansylcadaverine labeling and reduced expression of p62 . The autophagy inhibitor 3 methyladenine completely blocked the neuroprotective effect of Sim . Two hours after HI there was a reduction in the activity of mTORC1 and a concomitant increase in that of mTORC2 . Sim preconditioning further decreased the activity of mTORC1 but did not affect that of mTORC2 . However 24h after injury mTORC2 activity was significantly preserved in Sim treated rats . Sim preconditioning also prevented the depletion of SIRT1 induced by HI an effect that was completely blocked by 3MA . These data show that Sim preconditioning may modulate autophagy and survival pathways by affecting mTORC1 mTORC2 and SIRT1 activities . This study provides further preclinical evidence of the PC like effect of statins in brain tissue supporting their beneficial effects in improving stroke outcome after prophylactic treatments . | Simvastatin preconditioning potentiates autophagy in neonatal ischemic rats. The beneficial effect of simvastatin is impaired by blocking autophagy. mTORC1 mTORC2 and SIRT1 are essential players in simvastatin preconditioning. |
S0014488619302663 | Traumatic brain injury is a leading cause of death and disability in the US . Neural stem progenitor cells persist in the adult brain and represent a potential cell source for tissue regeneration and wound healing after injury . The Notch signaling pathway is critical for embryonic development and adult brain injury response . However the specific role of Notch signaling in the injured brain is not well characterized . Our previous study has established a Notch1CR2 GFP reporter mouse line in which the Notch1CR2 enhancer directs GFP expression in NSPCs and their progeny . In this study we performed closed head injury in the Notch1CR2 GFP mice to study the response of injury activated NSPCs . We show that CHI induces neuroinflammation cell death and the expression of typical TBI markers validating the animal model . In addition CHI induces cell proliferation in GFP cells expressing NSPC markers e.g . Notch1 and Nestin . A significant higher percentage of GFP astrocytes and GABAergic neurons was observed in the injured brain with no significant change in oligodendrocyte lineage between the CHI and sham animal groups . Since injury is known to activate astrogliosis our results suggest that injury induced GFP NSPCs preferentially differentiate into GABAergic neurons . Our study establishes that Notch1CR2 GFP transgenic mouse is a useful tool for the study of NSPC behavior in vivo after TBI . Unveiling the potential of NSPCs response to TBI will identify new therapeutic strategy for the treatment of brain trauma . | Notch1CR2 GFP transgenic mouse is a useful model to study NSPC behavior in TBI. TBI induces NSPC proliferation and differentiation in Notch1CR2 GFP mice. TBI induced Notch1CR2 GFP NSPCs preferentially differentiate into GABAergic neurons. |
S0014488619302675 | Multiple system atrophy is a fatal disorder with no effective treatment . MSA pathology is characterized by synuclein accumulation in oligodendrocytes the myelinating glial cells of the central nervous system . aSyn accumulation in oligodendrocytes forms the pathognomonic glial cytoplasmic inclusions of MSA . MSA aSyn pathology is also associated with motor and autonomic dysfunction including an impaired ability to sweat . MSA patients have abnormal CNS expression of glial cell line derived neurotrophic factor and brain derived neurotrophic factor . Our prior studies using the parent compound FTY720 a food and drug administration approved immunosuppressive for multiple sclerosis reveal that FTY720 protects parkinsonian mice by increasing BDNF . Our FTY720 derivative FTY720 Mitoxy is known to increase expression of oligodendrocyte BDNF GDNF and nerve growth factor but does not reduce levels of circulating lymphocytes as it is not phosphorylated so can not modulate sphingosine 1 phosphate receptors . To preclinically assess FTY720 Mitoxy for MSA we used mice expressing human aSyn in oligodendrocytes under a 2 3 cyclic nucleotide 3 phosphodiesterase promoter . CNP aSyn transgenic mice develop motor dysfunction between 7 and 9 mo and progressive GCI pathology . Using liquid chromatography mass spectrometry and enzymatic assays we confirmed that FTY720 Mitoxy was stable and active . Vehicle or FTY720 Mitoxy was delivered to wild type or Tg littermates from 8.511.5 mo by osmotic pump . We behaviorally assessed their movement by rotarod and sweat production by starchiodine test . Postmortem tissues were evaluated by qPCR for BDNF GDNF NGF and GDNF receptor RET mRNA and for aSyn BDNF GDNF and Iba1 protein by immunoblot . MicroRNAs were also assessed by qPCR . FTY720 Mitoxy normalized movement sweat function and soleus muscle mass in 11.5 mo Tg MSA mice . FTY720 Mitoxy also increased levels of brain GDNF and reduced brain miR 96 5p a miRNA that acts to decrease GDNF expression . Moreover FTY720 Mitoxy blocked aSyn pathology measured by sequential protein extraction and immunoblot and microglial activation assessed by immunohistochemistry and immunoblot . In the 3 nitropropionic acid toxin model of MSA FTY720 Mitoxy protected movement and mitochondria in WT and CNP aSyn Tg littermates . Our data confirm potent | CNP aSyn MSA mice develop age onset motor and sweat dysfunction synucleinopathy and neuroinflammation. FTY720 Mitoxy improves movement muscle mass and sweat function in MSA mice. FTY720 Mitoxy reduces MSA mouse synucleinopathy and neuroinflammation. FTY720 Mitoxy also increases RET and GDNF mRNA while reducing GDNF modulating miR 96 5p levels |
S0014488619302687 | Paclitaxel is widely used in the treatment of common cancers like breast ovarian and lung cancer . Although highly effective in blocking tumor progression paclitaxel also causes peripheral neuropathy as a side effect in 60 70 of chemotherapy patients . Recent efforts by numerous labs have aimed at defining the underlying mechanisms of paclitaxel induced peripheral neuropathy . In | Inflammation ion channel function and perturbed calcium homeostasis contribute to paclitaxel induced neuropathic pain. Reactive oxygen species and altered microtubule function are common in models of paclitaxel induced peripheral neuropathy. Genetic studies reveal conserved PIPN genes in animal models and patients which may reveal new clinical targets. |
S0014488619302754 | MicroRNA 592 has been reported to play a significant role in mediating neuronal activity but its possible link with Alzheimer s disease remains unclear . We aimed to explore the mechanism of miR 592 in oxidative stress injury of astrocytes from AD rat models induced by D galactose or A | A rat model is used to explore roles of miR 592 and KIAA0319 on AD. miR 592 is overexpressed in AST of AD rats. miR 592 inhibits Keap1 Nrf2 ARE signaling pathway by down regulating KIAA0319. Activation of Keap1 Nrf2 ARE signaling pathway promotes antioxidant enzyme activities. The study provides theoretical basis for the treatment of AD. |
S001448861930281X | Fabry disease is an X linked lysosomal storage disorder that leads to cellular globotriaosylceramide accumulation due to mutations in the gene encoding galactosidase A . Trigger induced acral burning pain is an early FD symptom of unknown pathophysiology . We aimed at investigating the potential role of skin fibroblasts in nociceptor sensitization . We enrolled 40 adult FD patients and ten healthy controls who underwent a 6 mm skin punch biopsy at the lower leg . Dermal fibroblasts were cultivated and analyzed for Gb3 load . Fibroblast electrical activity was assessed using patch clamp analysis at baseline and upon incubation with agalsidase for 24h . We investigated gene expression of C Total Gb3 load was higher in FD fibroblasts than in control fibroblasts Gb3 deposition in skin fibroblasts may impair K | Gb3 load is elevated in Fabry dermal fibroblasts. Gb3 induces immediate reduction of K. 1.1 channel activity. Notch1 pathway is activated in fibroblasts of male Fabry patients with pain. Cytokine gene expression is elevated in fibroblasts of male Fabry patients with pain |
S0014488619302821 | Traumatic brain injury is one of the most common causes of death and disability worldwide . We investigated whether inhibition of p53 using pifithrin or PFT provides neuroprotective effects via p53 transcriptional dependent or independent mechanisms respectively . Sprague Dawley rats were subjected to controlled cortical impact TBI followed by the administration of PFT or PFT at 5h after TBI . Brain contusion volume as well as sensory and motor functions were evaluated at 24h after TBI . TBI induced impairments were mitigated by both PFT and PFT . Fluoro Jade C staining was used to label degenerating neurons within the TBI induced cortical contusion region that together with Annexin V positive neurons were reduced by PFT . Double immunofluorescence staining similarly demonstrated that PFT significantly increased HO 1 positive neurons and mRNA expression in the cortical contusion region as well as decreased numbers of 4 hydroxynonenal positive cells . Levels of mRNA encoding for p53 autophagy mitophagy anti oxidant anti inflammatory related genes and proteins were measured by RT qPCR and immunohistochemical staining respectively . PFT but not PFT significantly lowered p53 mRNA expression . Both PFT and PFT lowered TBI induced pro inflammatory cytokines mRNA levels as well as TBI induced autophagic marker localization . Finally treatment with PFT mitigated TBI induced declines in mRNA levels of PINK 1 and SOD2 . Our data suggest that both PFT and PFT provide neuroprotective actions through regulation of oxidative stress neuroinflammation autophagy and mitophagy mechanisms and that PFT in particular holds promise as a TBI treatment strategy . | Neuronal apoptosis in TBI engages separate transcriptional and mitochondrial p53 pathways. Inactivation of either pathway mitigates neuronal loss neuroinflammation behavior deficits. Inactivation of the p53 direct mitochondrial pathway provides greater benefits. |
S0014488619302833 | Low neuronal cAMP levels in adults and a further decline following traumatic central nervous system injury has been associated with the limited ability of neurons to regenerate . An approach to increase neuronal cAMP levels post injury is electrical stimulation . Stimulation as a tool to promote neuronal growth has largely been studied in the peripheral nervous system or in spared fibers of the CNS and this research suggests that a single session of electrical stimulation is sufficient to initiate a long lasting axonal growth program . Here we sought to promote plasticity and growth of the injured corticospinal tract with electrical cortical stimulation immediately after its spinal injury . Moreover given the importance of rehabilitative motor training in the clinical setting and in translating plasticity into functional recovery we applied training as a standard treatment to all rats . Our findings show that electrical cortical stimulation did improve recovery in forelimb function compared to the recovery in unstimulated animals . This recovery is likely linked to increased corticospinal tract plasticity as evidenced by a significant increase in sprouting of collaterals above the lesion site but not to increased regenerative growth through the lesion itself . | Adult rats were trained in a reaching task prior to unilateral cervical spinal lesion. The injury was directly followed by 30min of cortical electrical stimulation. Animals were assessed weekly in the reaching task for 5weeks post injury. The stimulated group showed greater functional recovery in the trained task. Stimulation induced increased corticospinal tract sprouting into grey matter. |
S0014488619302857 | After spinal cord injury the inhibitory molecules derived from scars at the lesion sites and the limited regenerative capacity of neuronal axons pose difficulties for the recovery after SCI . Remodeling of cytoskeleton structures including microtubule assembly and tubulin post translational modification are widely accepted to play a crucial role in initiation of growth cone and regrowth of injured axon . Although increasing studies have focused on the association between tubulin acetylation and autophagy due to the role of tubulin acetylation in organelles and substances transport there are no studies exploring the effect of tubulin acetylation on autophagy after spinal cord injury . Here we found that histone deacetylase 6 was significantly up regulated after SCI while inhibition of HDAC6 by Tubastatin A induced functional recovery after SCI . In view of enzyme dependent and independent mechanisms of HDAC6 to adjust diverse cellular processes such as autophagy the ubiquitin proteasome system and post translational modification of tubulin we mainly focused on the significance of HDAC6 in axonal regeneration and autophagy after SCI . Western blotting Co immunoprecipitation and immunofluorescence staining were conducted to showed that Tubastatin A treatment in nocodazole treated cells and mice suffering from SCI prompted acetylation and stabilization of microtubules and thus restored transport function which may contribute to restored autophagic flux and increased axonal length . Whereas inhibition of degradation of autolysosomes by bafilomycin A1 reversed functional recovery caused by Tubastatin A revealing the association between tubulin acetylation and autophagy which supports HDAC6 inhibition as a potential target for SCI treatment . | HDAC6 can affect microtubule system function by deacetylating tubulin. Decreased acetylation level of Tubulin induces axonal transport dysfunction. Inhibition of HDAC6 by Tubastatin A restores autophagic flux after SCI. Inhibition of HDAC6 by Tubastatin A promotes functional recovery after SCI. |
S0014488619302869 | Inflammasome contributes to ischemic brain injury by inducing pyroptosis and inflammation . The aim of this study is to unravel the mechanism of long non coding RNA maternally expressed gene 3 mediated regulation of absent in melanoma 2 inflammasome during cerebral ischemia reperfusion . In vivo middle cerebral artery occlusion rat model and in vitro oxygen glucose deprivation reperfusion treated neurocytes model were generated . TTC H E staining and TUNEL were performed to assess the cerebral ischemic injury . LDH and MTT assays were used to detect cell viability and cytotoxicity . qRT PCR was used to detect the expression levels of MEG3 miR 485 and AIM2 . Immunohistochemistry and immunofluorescence were conducted to detect the AIM2 expression . ELISA and Western blotting were performed to determine the secretion and protein levels of inflammasome signaling proteins . Dual luciferase reporter assay and Ago2 RIP were used to validate the direct interaction among MEG3 miR 485 and AIM2 . In both MCAO rats and OGD R treated neurocytes MEG3 and AIM2 were significantly up regulated whereas miR 485 was down regulated . MCAO induces pyroptosis and release of IL 1 and IL 18 in ischemia brain . MEG3 acted as a molecular sponge to suppress miR 485 and AIM2 was identified as a direct target of miR 485 . Knockdown of MEG3 inhibited OGD R induced pyroptosis and inflammation and lack of MEG3 inhibited caspase1 signaling and decreased the expression of AIM2 ASC cleaved caspase1 and GSDMD N. While overexpression of MEG3 exerted opposite effects . MEG3 miR 485 AIM2 axis contributes to pyroptosis via activating caspase1 signaling during cerebral I R suggesting that this axis may be a potent therapeutic target in ischemic stroke . | MEG3 and AIM2 are up regulated whereas miR 485 is down regulated in the in vivo and in vitro models of cerebral I R. MEG3 positively regulates the expression of AIM2 via sponging miR 485. Knockdown of MEG3 inhibits OGD R induced pyroptosis and inflammation by directly up regulating miR 485. Knockdown of MEG3 alleviated AIM2 mediated pyroptosis via inhibiting caspase1 signaling. |
S0014488619302894 | A major gap in the field of ischemic preconditioning is whether or not long lasting neuroprotection can be achieved . Moreover the specific mechanisms underlying IPC and how they can be translated into the clinic remain uncertain . To fill these gaps we tested the hypothesis that IPC exerts long lasting structural and functional neuroprotection against ischemic stroke through the master gatekeeper of antioxidant defenses nuclear factor erythroid 2 related factor 2 . We also tested whether the brain could be pharmaceutically preconditioned with a potent and blood brain barrier permeable Nrf2 activator 2 cyano 3 12 dioxo oleana 1 9 dien 28 trifluoethyl amide . IPC was induced by transient middle cerebral artery occlusion for 12min and ischemic stroke was generated by MCAO for 60min in wild type or Nrf2 knockout mice . Sensorimotor function learning memory skills and brain tissue loss were measured up to 35days after stroke . Primary rodent cortical neurons from wildtype and Nrf2 KO mice were subjected to lethal oxygen glucose deprivation or a brief OGD episode as a preconditioning stimulus before OGD . Cell viability death lipid electrophile generation and Nrf2 activation were measured . CDDO TFEA or its vehicle was administered in vivo for three consecutive days before MCAO . Tissue loss and neurological tests were performed 35days after stroke . IPC significantly reduced sensorimotor deficits post stroke cognitive impairments and brain tissue loss 35days after MCAO in WT mice . These enduring protective effects of IPC were inhibited in Nrf2 KO mice . In neuronal cultures PC also endowed primary neurons with ischemic tolerance against OGD induced cell death an effect that was abolished by loss of Nrf2 expression in KO neurons . PC induced the generation of low levels of lipid electrophiles and led to activation of the Nrf2 pathway . The mechanism underlying IPC may be translatable as exogenous administration of the Nrf2 activator CDDO TFEA significantly reduced neurological dysfunction and ischemic brain damage after MCAO . IPC provides long lasting neuroprotection against ischemic brain injury and post stroke cognitive dysfunction . Nrf2 activation plays a key role in this beneficial outcome and is a promising therapeutic target for the attenuation of ischemic brain injury . | IPC provides long lasting protection against sensorimotor and cognitive impairments and tissue loss after ischemic stroke. IPC afforded neuroprotection is reduced in Nrf2 knockout mice. Mechanistically IPC induces sublethal generation of lipid electrophiles leading to endogenous activation of Nrf2 pathway. Pharmacological activation of Nrf2 provides a similar degree of long term protection in translational studies. Nrf2 is a promising therapeutic target with enduring protective effects against ischemic stroke. |
S0014488619302936 | IL 17 producing CD4 T cells cells increase significantly with disease severity in myasthenia gravis patients . To suppress the generation of Th17 cells we examined the effect of inhibiting retinoic acid receptor related orphan receptor C a Th17 specific transcription factor critical for differentiation . ROR inhibition profoundly reduced Th17 cell frequencies including IFN and IL 17 co producing pathogenic Th17 cells . Other T helper subsets were not affected . In parallel CD8 T cell subsets producing IL 17 and IL 17 IFN were increased in MG patients and inhibited by the ROR inhibitor . These findings provide rationale for exploration of targeted Th17 therapies including ROR inhibitors to treat MG patients . | Th17 cell frequencies are associated with disease severity in MG. ROR inhibitor suppresses the generation of IFN and IL 17 co producing CD4 T cells. IL 17 producing CD8 T cells are enhanced in MG and inhibited by ROR inhibitor. |
S0014488619302948 | Postoperative electrical stimulation improves nerve regeneration by decreasing staggered regeneration at the coaptation site . By contrast conditioning electrical stimulation accelerates axon extension . Given that both techniques can be delivered at the bedside a direct comparison of outcomes is of significant clinical importance . In this study we compared regeneration and reinnervation outcomes of CES PES a combination of CES and PES and a no stimulation control . Sprague Dawley rats were randomly divided into i CES ii PES iii CES PES and iv no stimulation . CES was delivered one week prior to nerve cut coaptation and PES was delivered immediately following nerve repair . Length of nerve regeneration was assessed at 7days post coaptation | CES accelerates nerve regeneration greater than PES or a combination of CES PES. CES promotes sensorimotor functional recovery greater than PES and CES PES. CES PES did not have a synergistic effect to promote nerve regeneration. |
S0014488619303061 | Parkinson s disease is a debilitating condition resulting in motor and non motor symptoms affecting approximately 10 million people worldwide . Currently there are no pharmacological treatments that can cure the condition or effectively halt its progression . The focus of PD research has been primarily on the neurobiological basis and consequences of dopamine neuron degeneration given that the loss of DA neurons projecting from the substantia nigra to the dorsal striatum results in the development of cardinal PD motor symptoms . Alternatively gastrointestinal dysfunction is well recognized in PD patients and often occurs prior to the development of motor symptoms . The gut microbiota which contains thousands of bacterial species play important roles in intestinal barrier integrity and function metabolism immunity and brain function . Pre clinical and clinical studies suggest an important link between alterations in the composition of the gut microbiota and psychiatric and neurological conditions including PD . Several reports have documented gut dysbiosis and alterations in the composition of the gut microbiota in PD patients . Therefore the goal of this study was to explore the contribution of the gut microbiota to the behavioral and neurochemical alterations in a rodent toxin model of DA depletion that reproduces the motor symptoms associated with PD . We observed that chronic treatment of adult rats with non absorbable antibiotics ameliorates the neurotoxicity of 6 hydroxydopamine in a unilateral lesion model . Specifically immunohistochemistry against the dopaminergic neuron marker tyrosine hydroxylase showed an attenuation of the degree of 6 OHDA induced dopaminergic neuron loss in antibiotic treated animals compared to control animals . In addition we observed a reduction in the expression of pro inflammatory markers in the striatum of antibiotic treated animals . The degree of motor dysfunction after 6 OHDA was also attenuated in antibiotic treated animals as measured by paw rearing measurements in the cylinder test forepaw stepping test and ipsilateral rotations observed in the amphetamine induced rotation test . These results implicate the gut microbiota as a potential contributor to pathology in the development of PD . Further studies are necessary to understand the specific mechanisms involved in transducing alterations in the gut microbiota to changes in dopaminergic neuron loss and motor dysfunction . | Antibiotic treatment attenuates dopamine neuron degeneration in the 6 OHDA model of PD. The effect of 6 OHDA on dopamine neuron loss after antibiotic treatment correlates with an improvement in motor deficits. Brain pro inflammatory markers are associated with the protective effect of antibiotics on neuronal loss and motor behavior. |
S0014488619303103 | Traumatic spinal cord injury elicits a cascade of secondary injury mechanisms that induce profound changes in glia and neurons resulting in their activation injury or cell death . The resultant imbalanced microenvironment of acute SCI also negatively impacts regenerative processes in the injured spinal cord . Thus it is imperative to uncover endogenous mechanisms that drive these acute injury events . Here we demonstrate that the active form of bone morphogenetic protein 4 is robustly and transiently upregulated in acute SCI in rats . BMP4 is a key morphogen in neurodevelopment however its role in SCI is not fully defined . Thus we elucidated the ramification of BMP4 upregulation in a preclinical model of compressive contusive SCI in the rat by employing noggin an endogenous antagonist of BMP ligands and LDN193189 an intracellular inhibitor of BMP signaling . In parallel we studied cell specific effects of BMP4 on neural precursor cells oligodendrocyte precursor cells neurons and astrocytes | Active BMP4 is transiently upregulated in acute spinal cord injury in rats. BMP4 contributes to inhibitory microenvironment by promoting CSPG expression. BMP4 promotes cell death and lipid peroxidation. Blockade of BMP4 enhances oligodendrogenesis and remyelination following SCI. |
S0014488619303115 | Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is a rare slowly progressive white matter disease caused by mutations in the mitochondrial aspartyl tRNA synthetase . While patients show characteristic MRI T2 signal abnormalities throughout the cerebral white matter brainstem and spinal cord the phenotypic spectrum is broad and a multitude of gene variants have been associated with the disease . Here | Neuronal loss of. in mice results in a slow and progressive neurodegeneration. induced degeneration is preceded by activation of several immune pathways. Neuronal. mutant mice may be useful for the testing of therapeutics targeting the pediatric leukodystrophy LBSL. |
S0014488619303127 | Recordings from infants who died suddenly and unexpectedly demonstrate the occurrence of recurring apneas ineffective gasping and finally failure to restore eupnea and arouse prior to death . Immunohistochemical and autoradiographic data demonstrate a constellation of serotonergic defects in the caudal raphe nuclei in infants who died of Sudden Infant Death Syndrome . The purpose of this review is to synthesize what is known about adaptive responses of the infant to severely hypoxic conditions which unleash a flood of neuromodulators that inhibit cardiorespiratory function thermogenesis and arousal and the emerging role of serotonin which combats this cardiorespiratory inhibition to foster autoresuscitation eupnea and arousal to ensure survival following an hypoxic episode . The laryngeal and carotid body chemoreflexes are potent in newborns and infants and both reflexes can induce apnea and bradycardia which may be adaptive initially but must be terminated if an infant is to survive . Serotonin has a unique ability to touch on each of the processes that may be required to recover from hypoxic reflex apnea gasping the restoration of heart rate and blood pressure termination of apneas and eventually stimulation of eupnea and arousal . Recurrent apneic events bradycardia ineffective gasping and a failure to terminate apneas and restore eupnea are observed in animals harboring defects in the caudal serotonergic system models all of these phenotypes are reminiscent of and compatible with the cardiorespiratory recordings made in infants who subsequently died of SIDS . The caudal serotonergic system provides an organized multi pronged defense against reflex cardiorespiratory inhibition and the hypoxia that accompanies prolonged apnea bradycardia and hypotension and any deficiency of caudal serotonergic function will increase the propensity for sudden unexplained infant death . | Apnea and bradycardia can be an appropriate response to hypoxia in infants when a ventilatory response cannot be maintained. Autoresuscitation inhibition of apnea restoration of eupnea and arousal are essential to terminate apnea and bradycardia. Infants at risk for SIDS may have heightened sensitivity of the reflex mechanisms precipitating apneas and bradycardias. The caudal serotonergic system supports all the processes necessary to terminate apnea and bradycardia. Serotonin from the caudal raphe facilitates gasping terminates reflex apnea stimulates eupnea and enhances cortical arousal |
S0014488619303139 | We tested the hypothesis that exposure to intermittent hypoxia during pregnancy would prolong the laryngeal chemoreflex and diminish the capacity of serotonin to terminate the LCR . Prenatal exposure to IH was associated with significant prolongation of the LCR in younger anesthetized postnatal day rat pups age P8 to P16 compared to control room air exposed rat pups of the same age . Serotonin microinjected into the NTS shortened the LCR in rat pups exposed to RA during gestation but 5 HT failed to shorten the LCR in rat pups exposed to prenatal IH . Given these observations we tested the hypothesis that prenatal hypoxia would decrease binding to 5 HT | We tested the hypothesis that intermittent intrauterine hypoxia IH would prolong laryngeal chemoreflex LCR apnea. Prenatal exposure to IH was associated with prolongation of the LCR in younger postnatal P rat pups age P8 to P16 but not older pups. Serotonin 5 HT Microinjected serotonin in the nucleus of the solitary tract shortened the LCR in pups exposed to room air but not in pups exposed to prenatal IH. The 5 HT. receptor binding in the nucleus of the solitary tract was reduced in IH exposed pups age P8 to P12 but not in RA exposed ups of the same age. Prenatal IH sensitized the LCR reduce 5 HT. receptor binding and blunted serotonergically mediated termination of the LCR. |
S0014488619303140 | Secondary degeneration following an initial injury to the central nervous system results in increased tissue loss and is associated with increasing functional impairment . Unilateral partial dorsal transection of the adult rat optic nerve has proved to be a useful experimental model in which to study factors that contribute to secondary degenerative events . Using this injury model we here quantified the protective effects of intravitreally administered bi | AAV2 BDNF protects retinal ganglion cells after partial optic nerve injury. AAV2 encoding phospho resistant CRMP2 protects RGCs after partial optic nerve injury. Both vectors maintained important elements of myelin integrity in ventral optic nerve. AAV2 BDNF restored the number of smooth pursuit phases of optokinetic nystagmus. |
S0014488620300078 | Salicylate intoxication is a cause of tinnitus and comorbidly associated with anxiety in humans . In a previous work we showed that salicylate induces anxiety like behavior and hippocampal type 2 theta oscillations in mice . Here we investigate if the anxiogenic effect of salicylate is dependent on age and previous tinnitus experience . We also tested whether a single dose of DMT can prevent this effect . Using microwire electrode arrays we recorded local field potential in young and old mice to study the electrophysiological effect of tinnitus in the ventral hippocampus and medial prefrontal cortex in an open field arena and elevated plus maze 1 | Salicylate causes anxiety only when animals are normal hearing nave to tinnitus. Type 2 theta in anxiety spreads from the ventral hippocampus to the medial prefrontal cortex. Type 2 theta and slow gamma are complementary encoding safety and danger respectively during anxiety. 5 MeO DMT can prevent anxiety driven by tinnitus. |
S001448862030008X | Epidemiological studies suggest that chronic periodontitis is closely associated with the incidence and progression of cognitive impairment . The present study investigated the causal relationship between CP and cognitive decline and the underlying mechanism in mice . Long term ligature around the left second maxillary molar tooth was used to induce CP in mice . Severe alveolar bone loss and inflammatory changes were observed in gingival tissues accompanied by progressive cognitive deficits during a 12 month period . We also observed cerebral neuronal and synaptic injury and glial activation in this mouse model of CP . Furthermore CP mice exhibited significant dysbiosis of the oral and gut microbiota disruption of the intestinal barrier and blood brain barrier increases in the serum contents of proinflammatory cytokines and lipopolysaccharide and increases in brain LPS levels Toll like receptor 4 expression nuclear factor B nuclear translocation and proinflammatory cytokine mRNA levels . These results indicate that CP may directly induce progressive cognitive decline and its mechanism is probably related to microbiota gut brain axis disorders LPS TLR4 NF B signaling activation and neuroinflammatory responses in mice . Therefore the microbiota gut brain axis may provide the potential strategy for the prevention and treatment of CP associated cognitive impairment . | Chronic periodontitis CP mice displayed progressive cognitive deficits. Murine CP aggravated neuronal injury and neuroinflammation. Murine CP caused the oral and gut microbiota dysbiosis. Murine CP induced intestinal barrier damage and inflammation. Murine CP injured blood brain barrier and activated TLR4 pathway in the brain. |
S0014488620300091 | Preconditioning peripheral nerve injury primes the sensory neurons in the dorsal root ganglia to acquire axon regeneration competence . Transcription of a large set of regeneration associated genes contributes to the enhanced intrinsic axonal regeneration capacity . However the mechanism underlying the coordinated upregulation of RAGs orchestrated by preconditioning injury is unclear . We sought to determine potential influence of DNA methylation change on transcriptional activation of RAGs in the L4 L6 DRGs following sciatic nerve injury . Genome wide sequencing revealed that about 20 of the methylated DNA fragments were differentially methylated and 3000 genes contained differentially methylated regions . Not only demethylation but also increased methylation was observed to a similar extent . The change in the global DNA methylation did not correlate with the gene expression level of most genes including the well documented RAGs . However pharmacological inhibition or activation of DNA methylation markedly attenuated the axon growth capacity of the preconditioned DRG neurons . Pharmacological perturbation of DNA methylation resulted in simultaneous downregulation of many highly overlapping non transcription factor RAGs which was accompanied by a concurrent robust upregulation of SOCS3 and Serpine1 . Overexpression of SOCS3 and Serpine1 in the DRG neurons overrode injury induced axon growth competence corroborating their roles as the negative regulators of axon regeneration . We conclude that the injury induced global alteration of DNA methylome strongly influences the axon growth competence in preconditioned DRG neurons . Our results also suggest a possibility that perturbing DNA methylome changes might lead to the upregulation of negative regulator RAGs thereby attenuating axon growth capacity . | Preconditioning peripheral nerve injury led to substantial changes in DNA methylation in dorsal root ganglia DRGs . The global changes in DNA methylation were not correlated with the level of gene expression measured by RNA seq. Pharmacological inhibition or activation of DNA methylation attenuated axon growth competence of conditioned DRG neurons. Pharmacological perturbations downregulated non transcription factor RAGs accompanied by upregulation of SOCS3 and Serpine1. Overexpression of SOCS3 and Serpine1 in DRG neurons overrode injury induced axon growth competence. |
S0014488620300108 | Physical exercise can reduce the cognitive decline associated with traumatic brain injury yet little is known about the optimal administration schedules . Here different protocols of voluntary wheel running were evaluated for their effects on object recognition memory neuroprotection NeuN | Early and delayed voluntary wheel running reduce memory deficits after TBI in rats. Early exercise attenuates hippocampal microglial reactivity and neuron loss. Restored neurogenesis mediates memory recovery by close to training exercise. Moderate amounts of daily exercise lead to the highest neurogenesis levels. |
S0014488620300121 | In humans the majority of sustained traumatic brain injuries are classified as mild and most often a result of a closed head injury . The effects of a non penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction which could be worsened by repeated head injury . Clinical neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs . However the link between p tau and CHI in rodents remains controversial . To address this question experimentally we induced a single CHI or two CHIs to WT or rTg4510 mice . We found that 2 CHI increased tau phosphorylation in WT mice and rTg4510 mice . Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2 CHI mice that had partially resolved in the 1 CHI mice . Moreover using Manganese Enhanced Magnetic Resonance Imaging with R1 mapping a novel functional neuroimaging technique we found greater deficits in the rTg4510 mice following 2 CHI compared to 1 CHI . To integrate our findings with prior work in the field we conducted a systematic review of rodent mild repetitive CHI studies . Following Prisma guidelines we identified 25 original peer reviewed papers . Results from our experiments as well as our systematic review provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies however changes in p tau levels are not universally reported . Together our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI but the direct link between the worsened outcome and elevated p tau could not be established . | Chronic cognitive deficits are worsened following repetitive CHIs in WT mice. Functional neuroimaging deficits were found in the rTg4510 mice following a repetitive but not single CHI. Evidence that p tau was a driver in the repetitive CHI phenotypes could not be established. |
S0014488620300273 | The persistent unresponsiveness of many of the acquired epilepsies to traditional antiseizure medications has motivated the search for prophylactic drug therapies that could reduce the incidence of epilepsy in this at risk population . These studies are based on the idea of a period of epileptogenesis that can follow a wide variety of brain injuries . Epileptogenesis is hypothesized to involve changes in the brain not initially associated with seizures but which result finally in seizure prone networks . Understanding these changes will provide crucial clues for the development of prophylactic drugs . Using the repeated low dose kainate rat model of epilepsy we have studied the period of epileptogenesis following status epilepticus verifying the latent period with continuous EEG monitoring . Focusing on ultrastructural properties of the tripartite synapse in the CA1 region of hippocampus we found increased astrocyte ensheathment around both the presynaptic and postsynaptic elements reduced synaptic AMPA receptor subunit and perisynaptic astrocyte GLT 1 expression and increased number of docked vesicles at the presynaptic terminal . These findings were associated with an increase in frequency of the mEPSCs observed in patch clamp recordings of CA1 pyramidal cells . The results suggest a complex set of changes some of which have been associated with increasingly excitable networks such as increased vesicles and mEPSC frequency and some associated with compensatory mechanisms such as increased astrocyte ensheathment . The diversity of ultrastructural and electrophysiological changes observed during epileptogeneiss suggests that potential drug targets for this period should be broadened to include all components of the tripartite synapse . | The elements of ahippocampal tripartite synapse undergo dramatic changes at the ultrastructural level that have electrophysiological correlates after status epilepticu. Status epilepticus increases the readily releasable pool of vesicles and mEPSC frequency and decreases neuronal glutamate receptor expression. Following status epilepticus astrocytes have a reduced density of the glutamate transporter Glt 1. Disease modifying therapies to prevent epilepsy should take into consideration the roles neurons and astrocytes play in circuit excitability. |
S0014488620300327 | This study of medial gastrocnemius muscle and motor units after spinal cord hemisection and deafferentation in adult cats asked 1 whether the absence of muscle atrophy and unaltered contractile speed demonstrated previously in HSDA paralyzed peroneus longus muscles was apparent in the unloaded HSDA paralyzed MG muscle and 2 how ankle unloading impacts MG muscle and MUs after dorsal root sparing with foot placement during standing and locomotion . Chronic isometric contractile forces and speeds were maintained for up to 12months in all conditions but fatigability increased exponentially . MU recordings at 811months corroborated the unchanged muscle force and speed with significantly increased fatigability normal weights of MG muscle confirmed the lack of disuse atrophy . Fast MUs transitioned from fatigue resistant and intermediate to fatigable accompanied by corresponding fiber type conversion to fast oxidative and fast glycolytic accompanied by increased GAPDH enzyme activity in absolute terms and relative to oxidative citrate synthase enzyme activity . Myosin heavy chain composition however was unaffected . MG muscle behaved like the PerL muscle after HSDA with maintained muscle and MU contractile force and speed but with a dramatic increase in fatigability irrespective of whether all the dorsal roots were transected . We conclude that reduced neuromuscular activity accounts for increased fatigability but is not in of itself sufficient to promote atrophy and slow to fast conversion . Position and relative movements of hindlimb muscles are likely contributors to sustained MG muscle and MU contractile force and speed after HSDA and HSDA SP surgeries . | Cat hindlimb muscles were unloaded and their neuromuscular activity reduced by spinal cord hemisection and deafferentation. The unloaded fast twitch medial gastrocnemius MG muscle did not atrophy. The fatigability of the MG muscle and motor units increased whilst their contractile speeds and isometric forces were unchanged. Transition from fatigue resistant to fatigable fast motor units and fiber types is due to reduced neuromuscular activity. Hindlimb muscle position and relative movements are likely contributors to their maintained contractile force and speed |
S0014488620300339 | T lymphocytes have a multifaceted role in ischemic stroke but the majority of studies have been conducted in young mice which may limit the translational value of these findings . Previous studies have shown that aging results in T cell dysfunction leading to enhanced production of pro inflammatory cytokines and chemokines including interferon gamma and interferon gamma inducible protein . This study assessed the role of T cells and pro inflammatory factors on histologic and functional outcomes in an aged mouse model . Levels of IP 10 were measured in the brain and serum of young and aged male mice following middle cerebral artery occlusion or sham surgery . Additionally IP 10 levels were evaluated in stroke patients . To directly determine the role of brain infiltrating T cells after stroke a separate cohort of aged male and female animals received either an anti CD4 depletion antibody or IgG isotype control at 72 and 96h following experimental stroke . Behavioral assessments were performed on day 7 post MCAo . CD4 T cell depletion resulted in improved behavioral outcomes despite the lack of differences in infarct size between the isotype control and anti CD4 antibody treated stroke groups . Circulating IP 10 levels were increased in both humans and mice with age and stroke and depletion of CD4 T cells led to a reduction in IFN and IP 10 levels in mice . Since anti CD4 treatment was administered three days after stroke onset targeting this inflammatory pathway may be beneficial to aged stroke patients who present outside of the current time window for thrombolysis and thrombectomy . | Aging alters the immunological response to stroke. Aged animals and humans have poorer outcomes after stroke. The CD4 IFNy IP 10 pathway propagates the post stroke inflammatory cascade. CD4 depletion during peak inflammation resulted in improved functional outcomes in both male and female aged mice. Therapies targeting this inflammatory pathway should be explored. |
S0014488620300340 | Disruption of the blood brain barrier and subsequent cerebral edema formation is one of the major adverse effects of brain surgery leading to postoperative neurological dysfunction . Recently Mfsd2a has been shown to have a crucial role for the maintenance of BBB functions . In this study we aimed to evaluate the role of Mfsd2a on BBB disruption following surgical brain injury in rats . Rats were subjected to SBI by partial resection of the right frontal lobe . To evaluate the effect of Mfsd2a on BBB permeability and neurobehavior outcome following SBI Mfsd2a was either overexpressed or downregulated in the brain by administering Mfsd2a CRISPR activation or knockout plasmids respectively . The potential mechanism of Mfsd2a mediated BBB protection through the cav 1 Nrf 2 HO 1 signaling pathway was evaluated . Mfsd2a levels were significantly decreased while cav 1 Nrf 2 and HO 1 levels were increased in the right frontal perisurgical area following SBI . When overexpressed Mfsd2a attenuated brain edema and abolished neurologic impairment caused by SBI while downregulation of Mfsd2a expression further deteriorated BBB functions and worsened neurologic performance following SBI . The beneficial effect of Mfsd2a overexpression on BBB functions was associated with diminished expression of cav 1 increased Keap 1 Nrf 2 dissociation and further augmented levels of Nrf 2 and HO 1 in the right frontal perisurgical area leading to enhanced levels of tight junction proteins following SBI . The BBB protective effect of Mfsd2a was blocked by selective inhibitors of Nrf 2 and HO 1 . Mfsd2a attenuates BBB disruption through cav 1 Nrf 2 HO 1 signaling pathway in rats subjected to experimental SBI . | Mfsd2a levels decrease and contribute to the disruption of the BBB as well as worse neurologic outcomes following SBI. Mfsd2a overexpression alleviates BBB dysfunction by decreasing TJP degradation and improves neurologic outcome after SBI. Protective effect of Mfsd2a on BBB following SBI is at least partly mediated through Cav 1 Nrf 2 HO 1 pathway. |
S0014488620300376 | Ischemic stroke significantly perturbs neuronal homeostasis leading to a cascade of pathologic events causing brain damage . In this study we assessed acute stroke outcome after chemogenetic inhibition of forebrain excitatory neuronal activity . We generated hM4Di TG transgenic mice expressing the inhibitory hM4Di a Designer Receptors Exclusively Activated by Designer Drugs based chemogenetic receptor in forebrain excitatory neurons . Clozapine N oxide was used to activate hM4Di DREADD . Ischemic stroke was induced by transient occlusion of the middle cerebral artery . Neurologic function and infarct volumes were evaluated . Excitatory neuronal suppression in the hM4Di TG mouse forebrain was assessed electrophysiologically in vitro and in vivo based on evoked synaptic responses and in vivo based on occurrence of potassium induced cortical spreading depolarizations . Detailed characterization of hM4Di TG mice confirmed that evoked synaptic responses in both in vitro hippocampal slices and in vivo motor cortex were significantly reduced after CNO mediated activation of the inhibitory hM4Di DREADD . Further CNO treatment had no obvious effects on physiology and motor function in either control or hM4Di TG mice . Importantly hM4Di TG mice treated with CNO at either 10min before ischemia or 30min after reperfusion exhibited significantly improved neurologic function and smaller infarct volumes compared to CNO treated control mice . Mechanistically we showed that potassium induced cortical spreading depression episodes were inhibited including frequency and duration of DC shift in CNO treated hM4Di TG mice . Our data demonstrate that acute inhibition of a subset of excitatory neurons after ischemic stroke can prevent brain injury and improve functional outcome . This study together with the previous work in optogenetic neuronal modulation during the chronic phase of stroke supports the notion that targeting neuronal activity is a promising strategy in stroke therapy . | CNO treatment of hM4Di TG mice suppresses evoked synaptic responses in vitro and in vivo. hM4Di TG mice treated with CNO at 10min before ischemia improves stroke outcome. hM4Di TG mice treated with CNO at 30min after reperfusion improves stroke outcome. hM4Di mediated inhibition of excitatory neurons reduces K induced CSD activity in vivo. |
S0014488620300388 | One of the consistent pathologies associated with both clinical and experimental traumatic brain injury is axonal injury especially following mild traumatic brain injury . Several lines of experimental evidence have demonstrated a role for NAD metabolism in axonal degeneration . One of the enzymes that metabolizes NAD in axons is | APP accumulates in select white matter tracts after repeated mild closed head injury. APP accumulation is significantly attenuated after injury in. mice. White matter tract inflammation after rmCHI was decreased in. mice. Loss of Sarm1 improves motor and cognitive performance after injury. |
S001448862030039X | Spinal cord injury produces both locomotor deficits and sensory dysfunction that greatly reduce the overall quality of life . Mechanisms underlying chronic pain include increased neuro inflammation and changes in spinal processing of sensory signals with reduced inhibitory GABAergic signaling a likely key player . Our previous research demonstrated that spinal transplantation of GABAergic neural progenitor cells reduced neuropathic pain while intensive locomotor training could reduce development of pain and partially reverse already established pain behaviors . Therefore we evaluate the potential mutually beneficial anti hypersensitivity effects of NPC transplants cells in combination with early or delayed ILT . NPC transplants were done at 4weeks post SCI . ILT using a progressive ramping treadmill protocol was initiated either 5days post SCI or at 5weeks post SCI in male Sprague Dawley rats . Results showed that either ILT alone or NPCs alone could partially attenuate SCI neuropathic pain behaviors in both prevention and reversal paradigms . However the combination of ILT with NPC transplants significantly enhanced neuropathic pain reduction on most of the outcome measures including tests for allodynia hyperalgesia and ongoing pain . Immunocytochemical and neurochemical analyses showed decreased pro inflammatory markers and spinal pathology with individual treatments these measures were further improved by the combination of either early or delayed ILT and GABAergic cellular transplantation . Lumbar dorsal horn GABAergic neuronal and process density were nearly restored to normal levels by the combination treatment . Together these interventions may provide a less hostile and more supportive environment for promoting functional restoration in the spinal dorsal horn and attenuation of neuropathic pain following SCI . These findings suggest mutually beneficial effects of ILT and NPC transplants for reducing SCI neuropathic pain . | Intensive locomotor training ILT partially prevented or reversed SCI pain. GABAergic cellular transplantation partially prevented or reversed SCI pain. The combination of ILT and transplants enhanced the attenuation of SCI pain. Individual and combination therapy decreased pro inflammatory markers and spinal pathology. GABAergic neuronal and process density were normalized by the combination treatment. |
S0014488620300406 | Intracerebral hemorrhage patients frequently encounter cardiovascular complications which may contribute to increased mortality and poor long term outcome . ICH induces systemic oxidative stress and activates peripheral immune responses which are involved in the pathological cascade leading to cardiac dysfunction and heart failure after ICH . We have previously reported that ICH induces progressive cardiac dysfunction in mice without primary cardiac diseases . In this study we have investigated the role of immune response in mediating cardiac dysfunction post ICH in mice . Adult male C57BL 6J mice were randomly assigned to the following groups or chronic cardiac dysfunction . ICH induces significant neurological and cognitive deficits as well as acute and chronic cardiac dysfunction compared to sham control mice . Mice subjected to ICH Spx exhibit significantly improved neurological and cognitive function compared to ICH mice . Mice with ICH Spx also exhibit significantly improved acute and chronic cardiac function compared to ICH mice indicated by increased left ventricular ejection fraction and left ventricular fractional shortening decreased cardiac fibrosis decreased cardiomyocyte hypertrophy decreased cardiac infiltration of immune cells and decreased expression of inflammatory factor and oxidative stress in the heart . Our study demonstrates that splenectomy attenuates ICH induced neurological and cognitive impairment as well as ICH induced cardiac dysfunction in mice . Inflammatory cell infiltration into heart and immune responses mediated by the spleen may contribute to ICH induce acute and chronic cardiac dysfunction and pathological cardiac remodeling . | ICH increases cardiac deficit splenectomy attenuates ICH induced cardiac dysfunction in mice. Splenectomy decreases inflammatory cell infiltration into heart and reduces oxidative stress in the heart of ICH mice. Splenectomy attenuates neurological and cognitive impairment induced by ICH in mice. Spleen associated immune response mediates brain heart interaction after ICH in mice. |
S0014488620300418 | Accumulation of amyloid peptide and hyperphosphorylated tau in the brain is one of the pathological characteristics of Alzheimer s disease and attractive therapeutic targets in its treatment . In the present study the cognitive ability of 4 month old 3Tg AD mice significantly improved after 40days treatment with intraperitoneal injection of 2.25mg kg of SLOH which is a multifunctional carbazole based cyanine fluorophore . It reduced A deposition tau levels and its hyperphosphorylation by modulating AKT and promoting protein phosphatase 2A activity in the brain as well as in the primary neurons of 3Tg AD mice . Moreover SLOH attenuated synaptic deficit both in vitro and in vivo by regulating the Ca | SLOH improved the cognitive ability of young 3Tg AD mice. It delayed pathological development reduced A deposition tau levels and its phosphorylation by modulating AKT and PP2A activity. SLOH attenuated synaptic deficit both in vitro and in vivo by regulating the Ca. CaMKII CREB signaling pathway. |
S001448862030042X | Transsynaptic anterograde and retrograde degeneration of neurons and neural fibers are assumed to trigger local excitotoxicity and inflammatory processes . These processes in turn are thought to drive | Cortical stroke induces widespread degeneration of ipsilesional dopaminergic cells. Synaptic coupling is no prerequisite for post ischemic dopaminergic midbrain degeneration. Dopaminergic midbrain degeneration is likely not triggered by inflammation. Degeneration manifests independent of the pro inflammatory peptide Substance P. |
S0014488620300431 | Sleep fragmentation is an increase in sleep wake transitions without an overall decrease in total sleep time . Sleep fragmentation is well documented during acute and chronic hospitalization and can result in delirium and memory problems in children . Sleep fragmentation is also often noted in neurodevelopmental disorders . However it is unclear how sleep fragmentation independent of disease affects brain development and function . We hypothesized that acute sleep fragmentation during the neonatal period in otherwise healthy animals would result in neuroinflammation and would be associated with abnormalities in cognitive development . The orbital shaker method was used to fragment sleep for 72h in postnatal day 3 New Zealand white rabbit kits . To control for maternal separation the sham group was separated from the dam and maintained in the same conditions without undergoing sleep fragmentation . A nave control group remained with the dam . Kits underwent behavioral testing with novel object recognition and spontaneous alternation T maze tests at 23weeks post fragmentation and were sacrificed 350days after fragmentation . Sleep fragmentation resulted in acute and chronic changes in microglial morphology in the hippocampus and cortex and regional differences in mRNA expression of pro and anti inflammatory cytokines at 3 7 and 50days post fragmentation . Impaired novel object recognition and a longer latency in T maze task completion were noted in the fragmented kits . This was in spite of normalization of sleep architecture noted at 2months of age in these kits . The results indicate that transient neonatal sleep fragmentation results in short term and long term immune alterations in the brain along with diminished performance in cognitive tasks long term . | Transient sleep fragmentation during development leads to cognitive deficits later. Transient neonatal sleep fragmentation leads to persistent neuroinflammation. Sleep fragmentation affects normal cognitive development even if sleep architecture normalizes. |
S0014488620300443 | Status epilepticus is a clinical emergency that can lead to the development of temporal lobe epilepsy . The development and maintenance of spontaneous seizures in TLE are linked to calcium Ca | Ryanodine receptors are involved in neurodegeneration following status epilepticus. Blockade of intracellular calcium channels increases synaptic proteins after seizures. Neuroprotection preserves synaptic proteins levels after status epilepticus. |
S0014488620300455 | lysine is a basic amino acid that has been shown to exert neuroprotective effect . However the underlying mechanism remains to be elucidated . In this study we investigate how | lysine confers neuroprotection after mouse intracerebral hemorrhage injury. lysine promotes M2 microglial polarization and reduces inflammatory response. lysine upregulates miRNA 575 and downregulates PTEN. |
S0014488620300467 | Neurogenic differentiation 1 is mainlyexpressed in developing neurons where it plays critical roles in neuronal maturation and neurite elongation . The potential role and mechanism of NeuroD1 in adult axonal regeneration is not clear . The present study used synapsin Cre and AAV9 Flex vectors to conditionally overexpress NeuroD1 in adult spinal neurons and found that NeuroD1 overexpression significantly accelerated axonal regeneration and functional recovery after sciatic nerve injury . Further | NeuroD1 overexpression facilitates axonal regeneration after peripheral nerve injury. NeuroD1 overexpression reverses the functional impairment of the injured nerve. NeuroD1 overexpression upregulates the expression of BDNF TrkB and Spastin. |
S0014488620300479 | Neuropeptide Y is a 36 amino acid neuropeptide that is widely expressed in the central nervous system including the cerebral cortex nucleus accumbens and hypothalamus . We previously analyzed the behavior of transgenic mice exclusively expressing an unedited RNA isoform of the 5 HT | We generated regional and temporal specific NPY lesioned mice. Ablation of NPY neurons in the nucleus accumbens induced anxiety like behavior. Activation of NPY neurons in the nucleus accumbens induced anxiolytic like behavior. |
S0014488620300480 | Traumatic brain injury affects millions of individuals every year . Many of these injuries lead to lasting effects particularly impairments in domains broadly classified as executive functions such as impulse control and decision making . While these impairments have been historically associated with frontal brain damage other injuries such as concussion or parietal injury also contribute to similar dysfunction . However it is unknown whether animal models of TBI would replicate these broad effects that are observed in human patients . In the current study we delivered a unilateral parietal controlled cortical impact injury and assessed the performance of rats on a motoric task and a test of decision making and impulsivity . TBI rats demonstrated significant motor impairments on the rotarod task however this did not extend to difficulties inhibiting motor actions . In addition TBI caused chronic alterations to risk based decision making extending out to 12weeks post injury . Specifically rats with TBI preferred the riskiest and most suboptimal option over all others . The current data suggest that models of unilateral TBI are sufficient for replicating some aspects of executive dysfunction while others are limited to frontal damage . These models may be used to develop therapeutics targeted at the chronic post injury period when these symptoms often manifest in patients a critically understudied area in preclinical TBI research . | Unilateral parietal traumatic brain injury TBI increased choice of the riskiest alternatives. Unilateral parietal TBI caused motor impairments on the rotarod task but had no effect on motor impulsivity. Though primarily prefrontally mediated unilateral parietal TBI is sufficient to impair risk based decision making. |
S0014488620300509 | Amyotrophic lateral sclerosis is characterized by progressive degeneration of motor neurons . Astrocytes from diverse ALS models induce motor neuron death in co culture . Enhancing NAD | The approach used to enhance NAD. levels defines the biological outcome in ALS models. Nicotinamide riboside delays motor neuron degeneration in hSOD1. ALS mice. CD38 ablation does not confer protection in hSOD1. ALS mice. The expression of NMNAT2 and SIRT6 decreases in the spinal cord of ALS patients. |
S0014488620300522 | Mechanisms underlying affective and cognitive deficits in Parkinson s disease remain less studied than motor symptoms . Nucleus accumbens is affected in PD and due to its well known involvement in motivation is an interesting target in this context . Furthermore PD is frequently asymmetrical with side specific deficits aligning with evidences of accumbal laterality . We therefore used a 6 hydroxydopamine model to study the role of left and right NAc dopamine depletion in a battery of behavioral tasks . | Non motor and side specific symptoms of PD are frequently underappreciated. Behavioral impact of left and right dopamine depletion in the Nucleus Accumbens was analyzed. Right sided dopamine depletion potentiated habitual behaviors. Left sided dopamine depletion increased impulsivity. No alterations in motor and anxiety and depressive like behaviors were observed. |
S0014488620300546 | Ischemic stroke has become one of the main causes of death worldwide . MicroRNAs have been implicated in cerebral ischemia reperfusion injury and could serve as therapeutic targets . 5 Lipoxygenase is a key enzyme in the biosynthesis of leukotrienes and has been implicated in inflammatory central nerve system disorders . The objective of this study was to explore the neuroprotective effects of miR 193b 3p against focal cerebral I R injury in rats by regulating 5 LOX expression . Adult male Sprague Dawley rats were subjected to transient middle cerebral artery occlusion and reperfusion injury . The level of miR 193b 3p expression was observed in the rat cortical peri infarct region after focal cerebral I R injury . Bioinformatics analysis was used to predict the binding sites of miR 193b 3p and a dual luciferase reporter gene assay was applied to verify the potential interaction between 5 LOX mRNA and miR 193b 3p . Then rats were injected with a miR 193b 3p agomir or antagomir in the right lateral ventricle of the brain . Neurological deficit scores infarct volumes neuron damage and 5 LOX enzymatic activity and expression were measured . In an in vitro experiment cultured PC12 cells were exposed to oxygenglucose deprivation and reperfusion . OGD R induced cells were treated with a miR 193b 3p mimic or inhibitor and 5 LOX siRNA . Cell viability lactate dehydrogenase release apoptosis rate and 5 LOX expression were evaluated . The level of miR 193b 3p expression was increased in the cortical peri infarct region of rats with cerebral focal I R injury . The results of the dual luciferase reporter gene assay showed that a miR 193b 3p binding site was located in the 3 untranslated region of 5 LOX mRNA . Neurological deficit scores infarct volumes and neuronal injury were alleviated by miR 193b 3p agomir treatment but aggravated by miR 193b 3p antagomir . Furthermore leukotriene B4 cysteinyl leukotrienes and 5 LOX expression in the cortical peri infarct region of rats with focal cerebral I R injury were also downregulated by miR 193b 3p agomir treatment but upregulated by miR 193b 3p antagomir . In PC12 cells miR 193b 3p mimic significantly decreased OGD R induced cell death and reduced lactate dehydrogenase release and 5 LOX expression . In contrast miR 193b 3p inhibitor exacerbated OGD R induced injury in PC12 cells . Additionally the in vitro effects of miR 193b 3p inhibitor on OGD R induced cell injury were partially reversed by 5 LOX siRNA treatment . MiR 193b 3p has a potentially neuroprotective effect on focal cerebral I R induced injury by inhibiting 5 LOX expression . | The miR 193b 3p was significantly up regulated in the rat penumbra cerebral cortex responding to a ischemic stroke. miR 193b 3p could bind with the 3UTR 5 LOX mRNA and suppress its translation. Exogenous miR 193b 3p could reduce rat brain infarct size and promote neurological recovery after ischemic stroke. 5 LOX is a downstream component in the miR 193b 3p neuroprotective pathway. |
S0014488620300558 | Medial forebrain bundle deep brain stimulation has anti depressant effects clinically and in depression models . Currently therapeutic mechanisms of MFB DBS or how stimulation parameters acutely impact neurotransmitter release particularly dopamine are unknown . Experimentally MFB DBS has been shown to evoke dopamine response in healthy controls but not yet in a rodent model of depression . The study investigated the impact of clinically used stimulation parameters on the dopamine induced response in a validated rodent depression model and in healthy controls . The stimulation induced dopamine response in Flinders Sensitive Line FSL Linear mixed model analysis showed significant impact in both models following MFB DBS both at 130 and 60Hz with 100s pulse width in inducing dopamine response . Furthermore at 130Hz the evoked dopamine responses were different across the groups at the different pulse widths . The differential impact of MFB DBS on the induced dopamine response including different response patterns at given pulse widths is suggestive of physiological and anatomical divergence in the MFB in the pathological and healthy state . Studying how varying stimulation parameters affect the physiological outcome will promote a better understanding of the biological substrate of the disease and the possible anti depressant mechanisms at play in clinical MFB DBS . | MFB DBS evoked dopamine release in the Nucleus Accumbens. Evoked release profiles were different across the depression model and controls. Diverging release profile likely due to physiological anatomical differences in the MFB. |
S0014488620300637 | Chondroitin sulphate proteoglycans are inhibitors to axon regeneration and plasticity . A disintegrin and metalloproteinase with thrombospondin motifs 4 is a human enzyme that catalyses the proteolysis of CSPG protein cores . Infusion of ADAMTS4 into the damaged spinal cord was previously shown to improve functional recovery SCI however this therapy is limited in its enzyme form . Adeno associated viral vector gene therapy has emerged as the vector of choice for safe robust and long term transgene expression in the central nervous system . Here an AAV expression cassette containing ADAMTS4 under the control of the astrocytic GfaABC | ADAMTS4 is a mammalian endogenous CSPG degrading enzyme. An astrocyte selective AAV ADAMTS4 vector effectively expresses ADAMTS4. and. AAV ADAMTS4 decreased lesion size and increased fiber sprouting following SCI. The combination of hindlimb specific exercise rehabilitation improved functional recovery. |
S0014488620300649 | Interleukin 33 is known to activate the regulatory T lymphocytes which are negatively correlated with brain damage after ischemic stroke . In this study we aimed to investigate the role of Tregs in IL 33 mediated neuroprotection and elucidate the underlying mechanisms . In vivo male C57BL 6N mice were subjected to 60min of transient middle cerebral artery occlusion followed by daily administration of vehicle or IL 33 immediately after injury . Tregs were depleted by intraperitoneal administration of anti CD25 antibody . Behavioral changes brain edema neuronal injury Treg percentages and cytokine expression levels were investigated in each group . In vitro experiments primary mouse neuronal cells were subjected to oxygen glucose deprivation for 3h . Vehicle or drug conditioned Tregs were applied to the neurons at the time of induction of hypoxia . Neuronal apoptosis and cytokine expression were measured in each group . The results indicate that intraperitoneal administration of anti CD25Ab reduced CD4 CD25 Foxp3 Tregs increased infarct volume enhanced stroke induced cell death and decreased sensorimotor functions . Notably IL 33 increased CD4 CD25 Foxp3 Tregs in the spleen and brain . However blockading ST2 attenuated these effects of IL 33 . The supernatant of the IL 33 treated Treg culture reduced neuronal apoptosis and elevated the production of the Treg cytokines IL 10 IL 35 and transforming growth factor TGF | Anti CD25Ab caused a sharp decrease in Tregs aggravates brain edema and increases lesion volume. IL 33 exerts neuroprotective effects by increasing Tregs activation and infiltration after experimental ischemic stroke. ST2 competitive inhibition blocked IL 33 induced cellular and functional effects post stroke. |
S0014488620300650 | Paraoxonase 2 regulates reactive oxygen species production in mitochondria . Stimulating its expression has therapeutic potential for diseases where oxidative stress plays a significant role in the pathology . Evidence suggests that the anti diabetic drug pioglitazone may provide neuroprotection in Parkinson s disease Alzheimer s disease brain trauma and ischemia but the biochemical pathway responsible has not been fully elucidated . Here we report that pioglitazone for 5days significantly increased paraoxonase 2 expression in mouse striatum . Thus this result highlights paraoxonase 2 as a target for neuroprotective strategies and identifies pioglitazone as a tool to study the role of paraoxonase 2 in brain . | Paraoxonase 2 enhances mitochondria function and mitigates oxidative stress OS . OS contributes to a variety of disorders including Parkinson s Diseases and stroke. Pioglitazone is neuroprotective in a variety of neurological disorders. Pioglitazone stimulates PPAR and increases paraoxonase 2 expression. |
S0014488620300728 | Central neuropathic pain is the main symptom caused by spinal cord lesion in relapsing remitting multiple sclerosis but its management is still not effective . The transient receptor potential ankyrin 1 is a pain detecting ion channel involved in neuropathic pain development . Thus the aim of our study was to evaluate the role of TRPA1 in central neuropathic nociception induced by relapsing remitting experimental autoimmune encephalomyelitis mouse model . In this model we observed the development of similar clinical conditions of RRMS in C57BL 6 female mice through RR EAE using MOG | Relapsing remitting experimental autoimmune encephalomyelitis RR EAE causes nociception. Mechanical and cold allodynia induced by RR EAE model are reduced by pregabalin. Nociception in this model is reduced by TRPA1 antagonists and antioxidant. The TRPA1 agonists are increased in spinal cord tissue of induced mice. The RR EAE model did not alter. RNA expression in spinal cord. |
S001448862030073X | Sleep wake disturbances are both a risk factor and reported morbidity for intracerebral hemorrhage . ICH begins with a ruptured blood vessel and blood leakage into the parenchyma . In response to initial damage pathophysiological processes ensue that both exacerbate and repair damage . Inflammation is a hallmark process of ICH which includes microglia activation and increased cytokine signaling . Due to the dual role of cytokines as inflammatory signaling proteins and sleep regulatory substances we hypothesized that ICH would activate microglia increase SRSs and alter sleep wake patterns following an experimental model of ICH in the mouse . Male mice were randomized to receive an injection of collagenase ICH | We investigated inflammation and sleep wake patterns after ICH. Experimental ICH increased sleep and reduced wake was time of day dependent. Microglia were activated in the perihematomal region after experimental ICH. Inflammation may contribute to ICH induced sleep wake patterns. |
S0014488620300741 | Mitochondrial dysfunction is a pivotal event in many neurodegenerative disease states including traumatic brain injury and spinal cord injury . One possible mechanism driving mitochondrial dysfunction is glutamate excitotoxicity leading to Ca | Traumatic brain injury TBI results in mitochondrial impairment and neurodegeneration. Pioglitazone interacts with a mitochondrial membrane protein mitoNEET. mitoNEET is required for Pioglitazone to restore mitochondrial function in response to calcium insult. Pioglitazone restores bioenergetics and cortical tissue. interaction with mitoNEET following TBI. mitoNEET ligand NL 1 improves cognitive performance and cortical tissue sparing after TBI. |
S0014488620300753 | A variety of barriers ensures the protection of the peripheral nervous system from noxious blood borne or surrounding stimuli . In this review anatomy and functioning of the blood nerve barrier and the blood DRG barrier will be presented and key tight junction proteins described ZO 1 claudin 1 3 5 11 12 19 occludin and tricellulin . Different diseases can lead to or be accompanied by nerve barrier disruption impairment of nerve barriers in turn worsens pathology . Peripheral nerve injury diabetic neuropathy and inflammatory polyneuropathy cause an increased permeability of BNB and BDB . Knowledge and understanding of these mechanisms might ultimately lead to the invention of drugs to control barrier function and help ameliorating neurological diseases . | Both blood nerve barrier BNB and blood DRG barrier BDB are crucial in maintaining homeostasis of the peripheral nerve. Tight junction proteins have distinct localization and functions in these barriers. Neuropathies of different etiologies involve breakdown of BNB and or BDB. |
S0014488620300807 | Adult neurogenesis in hippocampus dentate gyrus is associated with the etiology on the early stage of Alzheimer s disease . Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of AD . Adiponectin a peptide hormone secreted by adipocytes plays a critical role in insulin sensitizing anti inflammatory and anti diabetic effects in peripheral tissues . We previously showed that AdipoRon as an agonist of adiponectin promotes neurite outgrowth under ischemia . However the role of AdipoRon on neural stem cells proliferation and cognitive dysfunction in the early stage of AD remains unknown . In this study we investigated the role of AdipoRon on cognitive dysfunction and deficits of NSCs proliferation in AD . The | AdipoRon ameliorates cognitive deficit of APP PS1 mice. AdipoRon alleviates A induced impairment of neuronal survival and NSC proliferation. AdipoRon promotes NSC proliferation through activating AMPK pathway. |
S0014488620300819 | The locus coeruleus is a pontine nucleus important for respiratory control and central chemoreception . It is affected in Alzheimer s disease and alteration of LC cell function may account for respiratory problems observed in AD patients . In the current study we tested the electrophysiological properties and CO | The majority of Alzheimers disease AD patients suffer from disturbed respiratory function. Chemosensitive Locus coeruleus neurons in adult rats are mainly inhibited by increased CO. The streptozotocin induced model of AD STZ AD had a significantly greater sensitivity to CO. CO. hyperpolarized resting membrane potential depolarized spike threshold and reduced A type K. current in STZ AD. |
S0014488620300820 | Low energy extracorporeal shock wave therapy has been used to treat various human diseases . Previous studies have shown that low energy ESWT promotes the release of various cell growth factors and trophic factors from the cells surrounding the target lesion . The aim of the current study was to determine whether the application of low energy ESWT upregulates the expression of brain derived neurotrophic factor and reduces neural tissue damage and functional impairment using a rat model of thoracic spinal cord contusion injury . We found that low energy ESWT promoted BDNF expression in the damaged neural tissue . The expression of BDNF was increased in various neural cells at the lesion . Additionally low energy ESWT increased the area of spared white matter and the number of oligodendrocytes in the injured spinal cord compared with untreated control animals . There were more axonal fibers around the injured site after the application of low energy ESWT than control . Importantly low energy ESWT improved the locomotor functions evaluated by both the BBB scale and ladder rung walking test in addition to the sensory function measured using a von Frey test . Moreover the electrophysiological assessment confirmed that the conductivity of the central motor pathway in the injured spinal cord was restored by low energy ESWT . These findings indicate that low energy ESWT promotes BDNF expression at the lesion site and reduces the neural tissue damage and functional impairment following spinal cord injury . Our results support the potential application of low energy ESWT as a novel therapeutic strategy for treating spinal cord injury . | Low energy extracorporeal shock wave therapy ESWT promoted BDNF expression after SCI. Low energy ESWT provide neuroprotective effect on the injured spinal cord. Locomotor and sensory functions following SCI were improved by low energy ESWT. Application of low energy ESWT may be a novel therapeutic strategy for treating SCI. |
S0014488620300832 | SARM1 is the central executioner of pathological axon degeneration promoting axonal demise in response to axotomy traumatic brain injury and neurotoxic chemotherapeutics that induce peripheral neuropathy . SARM1 is an injury activated NAD | cADPR is gene dosage sensitive biomarker of SARM1 activity. SARM1 is the major source of neuronal cADPR. cADPR is unlikely to promote axon degeneration. Mitochondrial dysfunction can trigger partial SARM1 activation. cADPR and NfL are complementary biomarkers of SARM1 dependent axon degeneration. |
S0014488620300844 | Our recent study investigated the role of collapsin response mediator protein 2 on dendritic spine morphology and memory function after traumatic brain injury . First we examined the density and morphology of dendritic spines in Thy1 GFP mice on the 1st day and 7th day after controlled cortical impact injury . The dendritic spine density in the hippocampus was decreased on P1D in which mainly mushroom type and thin type spines were lost . The density of dendritic spines was increased on P7D most of which were of the thin type . Next we explored the expression of CRMP2 on P1D and P7D . CRMP2 expression was decreased on P1D but the levels of the CRMP2 breakdown product were increased . On P7D the expression pattern was the opposite . Then we constructed CRMP2 overexpression and knockdown plasmids and transfected them into cultured neurons in vitro . CRMP2 increased the dendritic spine density of cultured neurons and the proportion of mushroom type spines while CRMP2 shRNA reduced the dendritic spine density and the proportion of mushroom type spines . To determine the role of CRMP2 in dendritic spines after TBI we stereotactically injected the CRMP2 overexpression and knockdown viruses into the hippocampus and found that CRMP2 increased the dendritic spine density and the proportion of mushroom type spines after TBI . Meanwhile as suggested by the morphological changes fear conditioning behavioral experiments confirmed that CRMP2 improved memory deficits after TBI . | Reveal the changing relationship between CRMP2 expression and the morphology of spines. CRMP2 increases spine density and promotes recovery of mushroom type spines after TBI. CRMP2 improved memory deficit after TBI. |
S0014488620300856 | Adverse childhood experience is a major risk factor for the onset of depression in adulthood . Neuroinflammation characterized by microglial activation and cytokine secretion is involved in susceptibility to depression induced by early life stress . Jumonji domain containing protein 3 a trimethylated lysine 27 in histone 3 demethylase can be activated by nuclear factor kappa B further regulating the expression of pro inflammatory cytokines and resulting in neuroinflammation . However its involvement in susceptibility to early life stress related depression is unknown . In the current study maternal separation was utilized as a model of early life stress and systemic lipopolysaccharide administration in adulthood was used as a later life challenge . Depressive and anxiety like behaviors and memory impairment were detected by behavioral tests . Microglial activation pro inflammatory cytokine expression and NF B Jmjd3 and H3K27me3 expression were detected in the prefrontal cortex and hippocampus in both infant and adult rats . Meanwhile the Jmjd3 inhibitor GSK J4 was used as an intervention | MS induced short and long term depressive like behaviors and neuroinflammation. Infant and adult MS rats had higher levels of Jmjd3 in the PFC and HIP. MS rats treated with LPS in adulthood displayed serious behavioral dysfunction and neuroinflammation. Jmjd3 is involved in MS induced susceptibility to depressive disorders. |
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