Neuroprotection In Stroke Research Articles

Regulatory T-cells within bone marrow-derived stem cells actively confer immunomodulatory and neuroprotective effects against stroke

Regulatory T-cells (Tregs) may exert a neuroprotective effect on ischemic stroke by inhibiting both inflammation and effector T-cell activation. Transplantation of human bone marrow-derived stem cells (BMSCs) in ischemic stroke affords neuroprotection that results in part from the cells’ anti-inflammatory property. However, the relationship between Tregs and BMSCs in treatment of ischemic stroke has not been fully elucidated. Here, we tested the hypothesis that Tregs within the BMSCs represent active mediators of immunomodulation and neuroprotection in experimental stroke. Primary rat neuronal cells were subjected to an oxygen-glucose deprivation and reperfusion (OGD/R) condition. The cells were re-perfused and co-cultured with Tregs and/or BMSCs. We detected a minority population of Tregs within BMSCs with both immunocytochemistry (ICC) and flow cytometry identifying cells expressing phenotypic markers of CD4, CD25, and FoxP3 protein. BMSCs with the native population of Tregs conferred maximal neuroprotection compared to the treatment conditions containing 0%, 10%, and 100% relative ratio Tregs. Increasing the Treg population resulted in increased IL6 secretion and decreased FGF-β secretion by BMSCs. This study shows that a minority population of Tregs exists within the therapeutic BMSC population, which serves as robust mediators of the immunomodulatory and neuroprotective effect provided by BMSC transplantation.

Protective effect and mechanism of ginsenoside Rg1 in cerebral ischaemia-reperfusion injury in mice

BackgroundGinsenoside Rg1 is regarded as one of main bioactive compounds responsible for pharmaceutical actions of ginseng with little toxicity and has been shown to have possibly neuroprotective effects. However, the mechanism of its neuroprotection for acute ischemic stroke is still elusive. The purpose of present study is thus to assess the neuroprotective effects of the ginsenoside Rg1 against neurological injury in a mice model of cerebral ischemia/reperfusion (I/R), and then to explore the mechanisms for these neuroprotective effects. MethodsMices were pretreated with ginsenoside Rg1 20,40 mg kg−1 d−1, ig, for 7d, respectively, then subjected to cerebral ischenmia (middle cerebral artery occlusion) for 2 h and reperfusion for 22 h. The infarct volume and the neurological deficit were determined by TTC staining and Longa′s scoring, respectively. The protein expression of brain-derived neurotrophic factor (BDNF) was analyzed by Immunohistochemistry and Western blot, respectively. Interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) expression in serum was measured by ELISA kit. High-performance liquid chromatography (HPLC) was used to explore the contents of Glu and Asp. ResultsCompared with the ischemia/reperfusion group, ginsenoside Rg1 40 mg/kg group has significantly reduced infarct volume, neurological deficit scores (P < .05), Interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) contents in serum (p < .01, respectively), the contents of Glu and Asp (P < .01). Immunohistochemistry and Western blot indicated that ginsenoside Rg1 40 mg/kg group significantly increased brain-derived neurotrophic factor (BDNF) protein expression in the CA1 regions of the hippocampus (p < .01). ConclusionsGinsenoside Rg1 40 mg/kg has protective effects on cerebral injury induced by ischeamia/reperfusion, which might be related to the increased in the expression of BDNF in the hippocampal CA1 region, the down-regulation of the expression of IL-1β、IL-6 and TNF-α in serum, the decreases in the contents of Glu and Asp in the brain tissue.

Abstract WP255: Omega-3 Fatty Acids as a Treatment for Experimental Ischaemic Stroke: A Systematic Review and Meta-analysis

Introduction: The number of stroke patients arriving at hospital within a therapeutic timeframe is increasing, enabling earlier and more successful intervention with thrombolysis and thrombectomy. Despite promising animal data, no neuroprotectants have translated into clinical practice. Brain tissue contains a high amount of polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA), an omega-3 fatty acid essential for normal brain growth and cognitive function. As DHA plays a critical role in neuronal survival and synaptic function, and is also a potent modulator of brain inflammation, it is a strong candidate for a successful neuroprotectant in stroke. Aims: We therefore aimed to summarise the current evidence for omega-3 fatty acids as a treatment for experimental acute ischaemic stroke. Methods: A systematic literature review of papers reporting omega-3 administration in animal models of acute stroke was conducted using the CAMARADES systematic review facility (SyRF). 1173 titles were screened, 168 abstracts reviewed and data extracted from 15 studies. Data were extracted manually, and collated, organised and analysed within CAMARADES. Measures of study quality were recorded, reflecting current STAIR recommendations for pre-clinical studies. Pre-defined endpoints extracted included mortality, infarct volume and neurobehavioural score. Results: DHA reduced infarct volume with an effect size of 48.5%, (95% CI 32.2 - 65.5) compared to control treatments. Neurobehavioural score was improved by 34.8%,( 95% CI 21.8 - 47.7) in DHA treated animals. There was a decrease in mortality of 61% for DHA treated animals (OR 0.39, 95% CI 0.21-0.77(12 studies, no heterogeneity)). All studies used male animals, and no studies co-administered alteplase. Composition of omega-3 preparations was a source of significant heterogeneity (P&lt;0.05). Post hoc analysis showed laboratory group was also a significant source of heterogeneity. Conclusions: Current evidence suggests that DHA administration significantly improves outcome and decreases mortality in animal models of acute ischaemic stroke, providing support for further translational studies.

Abstract TP263: Activation of Endothelial p21-Activated Kinase 1 Provides Neuroprotection After Stroke

Stroke is a major cause of death and long-term disability. Pak1 is implicated in many neurological disorders as it has been suggested to promote neuronal survival. However, its function and mechanisms have not been investigated in stroke. We assessed the hypothesis that Pak1 provides neuroprotection in stroke by stimulating the secretion of brain-derived neurotrophic factor (BDNF) in endothelial cells. Transient focal ischemia was induced by middle cerebral artery occlusion (MCAO, 90 mins) in young WT male mice. Two doses of IPA3, a Pak1 specific inhibitor, were injected (i.p.) at 30 minutes prior to stroke and 1.5 hours after stroke. For mechanism studies, lentivirus (LV) encoding Pak1 or IPA3 was used to overexpress or pharmacologically inhibit Pak1 in mouse primary brain microvascular endothelial culture. Then the cells were subjected to OGD (16h) with 48 h re-oxygenation and conditioned media (Endo-CM) were collected subsequently. Mouse primary cortical neuron culture was treated with Endo-CM after OGD (90 mins) and neuronal death was assessed 24 hours later. Pak1 activation (phosphorylated Pak1) was observed in the ischemic hemispheres 6 and 72 hours after MCAO (p-Pak1: sham 94.5± 4.7% versus 6-hour stroke 192.5 ± 10.4% ; sham 94.5± 4.7% versus 72-hour stroke 254.4 ± 32.3%, n = 4 p/g, p&lt;0.05 for both). Administration of IPA3 increased brain infarct size assessed 24 hours after MCAO stroke. In endothelial cultures, overexpression of Pak1 increased BDNF secretion in Endo-CM after OGD (LV-GFP 22.7 ± 2.8 versus LV-Pak1 48.6± 5.5, n = 4 p/g, p&lt;0.05). Accordingly, inhibition of Pak1 attenuated levels of BDNF in Endo-CM (Vehicle 24.5 ± 1.5 versus IPA3 9.4± 0.7, n = 3 p/g, p&lt;0.05). Finally, treatment with Endo-CM collected from Pak1 overexpressing culture reduced neuronal death after OGD (LV-GFP 36 ± 2% versus LV-Pak1 10± 1%, n = 3 p/g, p&lt;0.05), while Endo-CM from cells treated with Pak1 inhibitor increased neuronal mortality (Vehicle 24± 7% versus IPA3 43± 2%, n = 3 p/g, p&lt;0.05). Taken together, we demonstrated that endothelial Pak1 provides neuroprotection after ischemia. Mechanically, our data revealed that activation of Pak1 stimulates endothelial production of a well-known potent neuroprotectant, BDNF.

Abstract TP94: Combined Chlorpromazine and Promethazine Induce Neuroprotective Hibernation Without Hypothermia in Experimental Stroke

Introduction: Hibernation, in which the lowering of metabolism and body temperature reduces the energetic needs of brain cells, has emerged as a frontier in the search for neuroprotective agents against ischemia. In fact, it has been partially achieved clinically with therapeutic hypothermia. Metabolically slowed, hibernation-like states lead to a decrease in ischemic damage and improved neurologic outcomes. However, decreasing body temperature can cause serious systemic complications. Thus, finding ways to induce a hibernation-like drop in metabolism without also inducing hypothermia is clinically important. It was shown that pharmacological hibernation with Chlorpromazine and Promethazine (C+P) resulted in decreased brain activity and decreased body temperature. Here, by isolating these two effects, and by investigating effects on NADPH oxidase (NOX), the key component in the pathway most central to oxidative injury during ischemia, we sought to determine whether the neuroprotective effect of C+P is dependent or independent from its effect on body temperature. Methods: Sprague-Dawley rats were subjected to 2h MCAO, and 6 or 24 h reperfusion, upon which rats received an IP injection of saline or C+P (8 mg/kg). Temperature was maintained at 37°C, or allowed to spontaneously change. Infarct volumes and neurological deficits were examined. Oxidative stress was determined by levels of ATP, lactate, NADH and reactive oxygen species (ROS). NOX activity and expression of NOX subunits (p47 phox , gp91 phox , p22 phox and p67 phox ) were measured at 6 and 24 h reperfusion. Results: In 2 h MCAO rats, body temperatures were significantly reduced by 1 0 C after C+P within 5 min. At 2 h, body temperatures reached 34 0 C and remained significantly low for up to 6 h. Following 6 and 24 h of reperfusion, C+P decreased infarct volume, neurological deficit, lactate and ROS levels, but increased ATP and NADH. NOX activity and subunit expressions were down-regulated. C+P-induced neuroprotection was not affected by maintaining temperature at 37 0 C. Conclusion: C+P administration provided neuroprotection in ischemic stroke independently of reductions in body temperature. Our results suggest temperature reduction may be a result of metabolic depression, rather than a cause.

Mechanisms of neuroprotection against ischemic insult by stress-inducible phosphoprotein-1/prion protein complex.

Stress-inducible phosphoprotein 1 (STI1) acts as a neuroprotective factor in the ischemic brain and its levels are increased following ischemia. Previous work has suggested that some of these STI1 actions in a stroke model depend on the recruitment of bone marrow-derived stem cells to improve outcomes after ischemic insult. However, STI1 can directly increase neuroprotective signaling in neurons by engaging with the cellular prion protein (PrPC ) and activating α7 nicotinic acetylcholine receptors (α7nAChR). Given that α7nAChR activation has also been involved in neuroprotection in stroke, it is possible that STI1 can have direct actions on neurons to prevent deleterious consequences of ischemic insults. Here, we tested this hypothesis by exposing primary neuronal cultures to 1-h oxygen-glucose deprivation (OGD) and reperfusion and assessing signaling pathways activated by STI1/PrPC . Our results demonstrated that STI1 treatment significantly decreased apoptosis and cell death in mouse neurons submitted to OGD in a manner that was dependent on PrPC and α7nAChR, but also on the activin A receptor 1 (ALK2), which has emerged as a signaling partner of STI1. Interestingly, pharmacological inhibition of the ALK2 receptor prevented neuroprotection by STI1, while activation of ALK2 receptors by bone morphogenetic protein 4 (BMP4) either before or after OGD was effective in decreasing neuronal death induced by ischemia. We conclude that PrPC /STI1 engagement and its subsequent downstream signaling cascades involving α7nAChR as well as the ALK2 receptor may be activated in neurons by increased levels of STI1. This signaling pathway protects neurons from ischemic insults.

Functional Comparison of Cultures of IPSC-Derived Human Neurons and Rodent Neurons

Functional Comparison of Cultures of IPSC-Derived Human Neurons and Rodent Neurons

Oncotic Cell Death in Stroke.

Oncotic cell death or oncosis represents a major mechanism of cell death in ischaemic stroke, occurring in many central nervous system (CNS) cell types including neurons, glia and vascular endothelial cells. In stroke, energy depletion causes ionic pump failure and disrupts ionic homeostasis. Imbalance between the influx of Na+ and Cl- ions and the efflux of K+ ions through various channel proteins and transporters creates a transmembrane osmotic gradient, with ensuing movement of water into the cells, resulting in cell swelling and oncosis. Oncosis is a key mediator of cerebral oedema in ischaemic stroke, contributing directly through cytotoxic oedema, and indirectly through vasogenic oedema by causing vascular endothelial cell death and disruption of the blood-brain barrier (BBB). Hence, inhibition of uncontrolled ionic flux represents a novel and powerful strategy in achieving neuroprotection in stroke. In this review, we provide an overview of oncotic cell death in the pathology of stroke. Importantly, we summarised the therapeutically significant pathways of water, Na+, Cl- and K+ movement across cell membranes in the CNS and their respective roles in the pathobiology of stroke.

Glibenclamide Enhances the Therapeutic Benefits of Early Hypothermia after Severe Stroke in Rats.

Glibenclamide (GBC) is an antidiabetic drug that is in a class of medications known as sulfonylureas, which play critical roles in attenuating brain edema and reducing mortality in ischemic stroke patients. Therapeutic hypothermia (TH) is another robust neuroprotectant that prevents brain swelling and improves the neurological outcomes of stroke patients. However, whether the combination of GBC and TH can be used as a reliable neuroprotectant in ischemic stroke remains largely unknown. We used the middle cerebral artery occlusion (MCAO) rat model as well as oxygen and glucose deprivation-reoxygenation (OGD/R) endothelial cells as ischemic stroke models to investigate the efficacy and mechanisms of treating ischemic stroke with the combination of GBC and TH. The serum glucose, mortality rate, neurobehavioral functions, tight junctions, endothelial cells and inflammatory cytokines were evaluated in the stroke models after treatment with GBC, TH or the combination of them. After 5-hour occlusion and subsequent reperfusion, rats exhibited a large volume of hemispheric swelling and a high mortality rate. Stroke rats treated with the combined therapy did not exhibit hypoglycemia. The combination of GBC and TH exhibited synergistic neuroprotective effects in stroke rats that were associated with greater reductions in edema volume, better improvement in neurobehavioral functions, prevention of tight junction loss, and reduction of expression of the inflammatory cytokines COX-2 and iNOS. In OGD/R endothelia cells, the combination reduced endothelial cell death. This study demonstrated that both GBC and TH are neuroprotective after the severe stroke; however, combined therapy with GBC and TH enhanced the efficiency and efficacy of the effects of TH and GBC in the treatment of ischemia. This combined therapy may facilitate the clinical translation of TH management for severe stroke. The combination of GBC and TH seems to be a feasible and promising clinical strategy to alleviate cerebral injury following severe stroke.

Sirt1 mediates improvement in cognitive defects induced by focal cerebral ischemia following hyperbaric oxygen preconditioning in rats.

Hyperbaric oxygen preconditioning (HBO-PC) has been proposed as a safe and practical approach for neuroprotection in ischemic stroke. However, it is not known whether HPO-PC can improve cognitive deficits induced by cerebral ischemia, and the mechanistic basis for any beneficial effects remains unclear. We addressed this in the present study using rats subjected to middle cerebral artery occlusion (MCAO) as an ischemic stroke model following HBO-PC. Cognitive function and expression of phosphorylated neurofilament heavy polypeptide (pNF-H) and doublecortin (DCX) in the hippocampus were evaluated 14 days after reperfusion and after short interfering RNA-mediated knockdown of sirtuin1 (Sirt1). HBO-PC increased pNF-H and DCX expression and mitigated cognitive deficits in MCAO rats. However, these effects were abolished by Sirt1 knockdown. Our results suggest that HBO-PC can protect the brain from injury caused by ischemia-reperfusion and that Sirt1 is a potential molecular target for therapeutic approaches designed to minimize cognitive deficits caused by cerebral ischemia.

TRPV1-mediated Pharmacological Hypothermia Promotes Improved Functional Recovery Following Ischemic Stroke

Hypothermia shows promise for stroke neuroprotection, but current cooling strategies cause undesirable side effects that limit their clinical applications. Increasing efforts have focused on pharmacological hypothermia as a treatment option for stroke. Previously, we showed that activation of a thermoregulatory ion channel, transient receptor potential vanilloid 1 (TRPV1), by dihydrocapsaicin (DHC) produces reliable hypothermia. In this study, we investigate the effects of TRPV1-mediated hypothermia by DHC on long-term ischemic stroke injury and functional outcome. Hypothermia initiated at 3.5 hours after stroke significantly reduced primary cortical injury. Interestingly, hypothermia by DHC also significantly reduced secondary thalamic injury, as DHC-treated stroke mice exhibited 53% smaller thalamic lesion size. DHC-treated stroke mice further demonstrated decreased neuronal loss and astrogliosis in the thalamus and less thalamic fiber loss by diffusion tensor imaging (DTI). Importantly, a single 8 hour treatment of hypothermia by DHC after stroke provided long-term improvement in functional outcome, as DHC-treated mice exhibited improved behavioral recovery at one month post-stroke. These findings indicate that TRPV1-mediated hypothermia is effective in reducing both primary cortical injury and remote secondary thalamic injury, and a single treatment can produce persistent effects on functional recovery. These data highlight the therapeutic potential for TRPV1 agonism for stroke treatment.

Antioxidant and pro-angiogenic effects of corilagin in rat cerebral ischemia via Nrf2 activation.

The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway has been considered as a potential target for neuroprotection in stroke. The aim of present study was to determine whether corilagin, a novel Nrf2 activator, can protect against ischemia-reperfusion injury and explore the underlying mechanism involved. In vivo, rats exposed to middle cerebral artery occlusion were applied to establish an ischemic stroke model. Posttreatment of corilagin significantly reduced infarct volumes and apoptotic cells as well as improved neurologic score after reperfusion, together with increased vascular density in the ischemic penumbra. Meanwhile, posttreatment with corilagin in MCAO rats significantly decreased malondialdehyde levels, restored the superoxide dismutase and glutathione activity, elevating the Nrf2, heme oxygenase-1, the vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression. However, consecutive intrathecal injection of short interference RNAs targeting Nrf2 at 24-h intervals 72 h before ischemia reduced the beneficial effects of corilagin. In primary cultured neurons, corilagin dose-dependently protected against oxygen and glucose deprivation-induced insult, but the protective effect of corilagin was attenuated by knockdown of Nrf2. In conclusion, these findings indicate that corilagin exerts protective effects against cerebral ischemic injury by attenuating oxidative stress and enhancing angiogenesis via activation of Nrf2 signaling pathway.

The application of nanoparticles for neuroprotection in acute ischemic stroke.

Stroke still represents one of the most common causes of death and disability worldwide. Acute ischemic stroke (AIS), caused by brain arterial occlusion resulting from a thrombus or embolus, is the most common form of stroke. However, current therapies in AIS are inadequate, and the only US FDA approved treatment is the thrombolytic drug Alteplase. Therefore, establishing effective therapeutic strategies for AIS is urgently needed. Using nanoparticle-based technologies to deliver neuroprotective agents to the ischemic area has attracted increasing attention of late. In this review, the important molecular pathological mechanisms in cerebral ischemia are briefly summarized, the potential of nanoparticulate drug-delivery systems for AIS intervention and recovery are introduced and problems in the medical application of nanoparticles will also be discussed.

Neuroprotection in stroke: the importance of collaboration and reproducibility

Acute ischaemic stroke accounts for 6.5 million deaths per year, and by 2030 will result in the annual loss of over 200 million disability-adjusted life years globally. There have been considerable recent advances in the gold standard of acute ischaemic stroke treatment, some aspects of which-aspirin to prevent recurrence, and treating patients in specialized stroke wards-are widely applicable. Recanalization of the occluded artery through thrombolysis and/or endovascular thrombectomy is restricted to only a small proportion of patients, due to contra-indications and the costs associated with establishing the infrastructure to deliver these treatments. The use of neuroprotective agents in stroke has been a notable failure of translation from medical research into clinical practice. Yet, with the advent of endovascular thrombectomy and the ability to investigate patients in much greater detail through advanced imaging modalities, neuroprotective agents can and should be re-examined as adjunct therapies to recanalization. In parallel, this requires appropriate planning on behalf of the preclinical stroke research community: there is a need to reinvestigate these therapies in a more collaborative manner, to enhance reproducibility through reduced attrition, improved reporting, and adopting an approach to target validation that more closely mimics clinical trials. This review will describe some of the novel strategies being used in stroke research, and focus on a few key examples of neuroprotective agents that are showing newfound promise in preclinical models of stroke therapy. Our primary aim is to give an overview of some of the challenges faced by preclinical stroke research, and suggest potential ways to improve translational success.

CCR6 (CC Chemokine Receptor 6) Is Essential for the Migration of Detrimental Natural Interleukin-17-Producing γδ T Cells in Stroke.

Immune-mediated tissue damage after stroke evolves within the first days, and lymphocytes contribute to the secondary injury. Our goal was to identify T-cell subpopulations, which trigger the immune response. In a model of experimental stroke, we analyzed the immune phenotype of interleukin-17 (IL-17)-producing γδ T cells and explored the therapeutic potential of neutralizing anti-IL-17 antibodies in combination with mild therapeutic hypothermia. We show that brain-infiltrating IL-17-positive γδ T cells expressed the Vγ6 segment of the γδ T cells receptor and were largely positive for the chemokine receptor CCR6 (CC chemokine receptor 6), which is a characteristic for natural IL-17-producing γδ T cells. These innate lymphocytes are established as major initial IL-17 producers in acute infections. Genetic deficiency in Ccr6 was associated with diminished infiltration of natural IL-17-producing γδ T cells and a significantly improved neurological outcome. In the ischemic brain, IL-17 together with tumor necrosis factor-α triggered the expression of CXC chemokines and neutrophil infiltration. Therapeutic targeting of synergistic IL-17 and tumor necrosis factor-α pathways by IL-17 neutralization and therapeutic hypothermia resulted in additional protective effects in comparison to an anti-IL-17 antibody treatment or therapeutic hypothermia alone. Brain-infiltrating IL-17-producing γδ T cells belong to the subset of natural IL-17-producing γδ T cells. In stroke, these previously unrecognized innate lymphocytes trigger a highly conserved immune reaction, which is known from host responses toward pathogens. We demonstrate that therapeutic approaches targeting synergistic IL-17 and tumor necrosis factor-α pathways in parallel offer additional neuroprotection in stroke.

Inhibition of Gelatinases (MMP-2 and MMP-9) by Withania somnifera Phytochemicals Confers Neuroprotection in Stroke: An In Silico Analysis.

A stroke or cerebrovascular accident is a serious, life-threatening medical condition that occurs when the blood supply to part of the brain is severely reduced or cut off, depriving brain tissue of oxygen and nutrients. Studies suggested that level of gelatinases (MMP-2 and MMP-9) usually increases in the brain after stroke. The elevated activity of gelatinases plays the deleterious role in ischemic stroke, hemorrhagic stroke and perinatal hypoxic-ischemic brain injury. Therefore, matrix metalloproteinase (MMP)-2 and MMP-9 inhibition have therapeutic importance in stroke condition. Present in silico study investigates whether Withania somnifera (WS) phytochemicals inhibit the MMP-2 and MMP-9 by binding to the catalytic domain, as similar to their inhibitor or not. For that, we performed molecular docking study to evaluate the gelatinases-inhibitory potential of 36 WS phytochemicals, which compared with gelatinases inhibitors viz. hydroxamic acid, quercetin, doxycycline, minocycline and reverse hydroxamate. The results suggest that 28 out of 36 WS phytochemicals show higher affinity for MMP-2 owing to bind with active site residues of S1'-pocket with lower binding energy and smaller inhibition constant (Ki) than considered inhibitors. As well as, withanolide G and withafastuosin E show higher affinity for MMP-9 than reverse hydroxamate inhibitor. These phytochemicals have neuroprotective potential as an inherently useful oral drug to combat ischemic and hemorrhagic stroke mediated by gelatinases.

XBP1 (X-Box-Binding Protein-1)-Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G.

Impaired protein homeostasis induced by endoplasmic reticulum dysfunction is a key feature of a variety of age-related brain diseases including stroke. To restore endoplasmic reticulum function impaired by stress, the unfolded protein response is activated. A key unfolded protein response prosurvival pathway is controlled by the endoplasmic reticulum stress sensor (inositol-requiring enzyme-1), XBP1 (downstream X-box-binding protein-1), and O-GlcNAc (O-linked β-N-acetylglucosamine) modification of proteins (O-GlcNAcylation). Stroke impairs endoplasmic reticulum function, which activates unfolded protein response. The rationale of this study was to explore the potentials of the IRE1/XBP1/O-GlcNAc axis as a target for neuroprotection in ischemic stroke. Mice with Xbp1 loss and gain of function in neurons were generated. Stroke was induced by transient or permanent occlusion of the middle cerebral artery in young and aged mice. Thiamet-G was used to increase O-GlcNAcylation. Deletion of Xbp1 worsened outcome after transient and permanent middle cerebral artery occlusion. After stroke, O-GlcNAcylation was activated in neurons of the stroke penumbra in young mice, which was largely Xbp1 dependent. This activation of O-GlcNAcylation was impaired in aged mice. Pharmacological increase of O-GlcNAcylation before or after stroke improved outcome in both young and aged mice. Our study indicates a critical role for the IRE1/XBP1 unfolded protein response branch in stroke outcome. O-GlcNAcylation is a prosurvival pathway that is activated in the stroke penumbra in young mice but impaired in aged mice. Boosting prosurvival pathways to counterbalance the age-related decline in the brain's self-healing capacity could be a promising strategy to improve ischemic stroke outcome in aged brains.

Supplementation with different teas from Camellia sinensis prevents memory deficits and hippocampus oxidative stress in ischemia-reperfusion

Memory and cognition impairments resultant of ischemic stroke could be minimized or avoided by antioxidant supplementation. In this regard, the neuroprotective potential of Green tea from Camellia sinensis has been investigated. However, there is a lack of information regarding the neuroprotective potential of others teas processed from the Camellia sinensis. Here we investigate the neuroprotective role of green, red, white and black tea on memory deficits and brain oxidative stress in a model of ischemic stroke in rats. Our findings show that green and red teas prevent deficits in object and social recognition memories, but only green tea protects against deficits in spatial memory and avoids hippocampal oxidative status and intense necrosis and others alterations in the brain tissue. In summary, green tea shows better neuroprotection in ischemic stroke than the others teas from Camellia sinensis.

Anesthetic Neuroprotection in Experimental Stroke in Rodents: A Systematic Review and Meta-analysis.

Patients undergoing endovascular therapy for acute ischemic stroke may require general anesthesia to undergo the procedure. At present, there is little clinical evidence to guide the choice of anesthetic in this acute setting. The clinical implications of experimental studies demonstrating anesthetic neuroprotection are poorly understood. Here, the authors evaluated the impact of anesthetic treatment on neurologic outcome in experimental stroke. Controlled studies of anesthetics in stroke using the filament occlusion model were identified in electronic databases up to December 15, 2015. The primary outcome measures, infarct volume, and neurologic deficit score were used to calculate the normalized mean difference for each comparison. Meta-analysis of normalized mean difference values provided estimates of neuroprotection and contributions of predefined factors: study quality, the timing of treatment, and the duration of ischemia. In 80 retrieved publications anesthetic treatment reduced neurologic injury by 28% (95% CI, 24 to 32%; P < 0.0001). Internal validity was high: publication bias enhanced the effect size by 4% or less, effect size increased with study quality (P = 0.0004), and approximately 70% of studies were adequately powered. Apart from study quality, no predefined factor influenced neuroprotection. Neuroprotection failed in animals with comorbidities. Neuroprotection by anesthetics was associated with prosurvival mechanisms. Anesthetic neuroprotection is a robust finding in studies using the filament occlusion model of ischemic stroke and should be assumed to influence outcomes in studies using this model. Neuroprotection failed in female animals and animals with comorbidities, suggesting that the results in young male animals may not reflect human stroke.

Neuroprotection In Acute Stroke

Stroke is the leading cause of adult disability and remains the third most common cause of death in industrialized nations. The concept of neuroprotection mainly came from the studies of the pathology and pathophysiology of ischemic brain injury. Greater understanding of the pathophysiology of neuronal damage in ischemic stroke has generated interest in neuroprotection as a management strategy. Neuroprotective agents in stroke treatment, have generated long-term interest that have the potential to preserve brain tissue and improve overall outcome. One arm of neuroprotective agents limits acute injury to neurons in the ischemic penumbra. Many of these agents modulate neuronal receptors to reduce release of excitatory neurotransmitters, which contribute to early neuronal injury. Other neuroprotective agents prevent potentially detrimental events associated with return of blood flow. Returning blood contains leukocytes that may occlude small vessels and release toxic products. In fact they should act targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. The past few decades have produced a plethora of negative neuroprotective trial results. The questions of feasibility and practicability cannot be resolved simultaneously. In the future, optimal therapy may be achieved by combining neuroprotective agents with complementary mechanisms. Relevant areas of interest include the search for safe and effective treatment strategies that combine neuroprotection reperfusion, better use of advanced brain imaging for patient selection, and wider implementation of prehospital conducted clinical trials.