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Stroke remains a leading cause of mortality; however, available therapeutics are limited. The study of ischemic tolerance, in paradigms such as resveratrol preconditioning (RPC), provides promise for the development of novel prophylactic therapies. The heavily oxidative environment following stroke promotes poly-ADP-ribose polymerase 1 (PARP1)-overactivation and parthanatos, both of which are major contributors to neuronal injury. In this study, we tested the hypothesis that RPC instills ischemic tolerance through decreasing PARP1 overexpression and parthanatos following in vitro and in vivo cerebral ischemia. To test this hypothesis, we utilized rat primary neuronal cultures (PNCs) and middle cerebral artery occlusion (MCAO) in the rat as in vitro and in vivo models, respectively. RPC was administered 2 days preceding ischemic insults. RPC protected PNCs against oxygen and glucose deprivation (OGD)-induced neuronal loss, as well as increases in total PARP1 protein, implying protection against PARP1-overactivation. Twelve hours following OGD, we observed reductions in NAD + /NADH as well as an increase in AIF nuclear translocation, but RPC ameliorated NAD + /NADH loss and blocked AIF nuclear translocation. MCAO in the rat induced AIF nuclear translocation in the ischemic penumbra after 24 h, which was ameliorated with RPC. We tested the hypothesis that RPC's neuroprotection was instilled through long-term downregulation of nuclear PARP1 protein. RPC downregulated nuclear PARP1 protein for at least 6 days in PNCs, likely contributing to RPC's ischemic tolerance. This study describes a novel mechanism by which RPC instills prophylaxis against ischemia-induced PARP1 overexpression and parthanatos, through a long-term reduction of nuclear PARP1 protein., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Women have a higher risk of having an ischemic stroke and increased cognitive decline after stroke as compared to men. The female sex hormone 17β-estradiol (E2) is a potent neuro- and cognitive-protective agent. Periodic E2 or estrogen receptor subtype-beta (ER-β) agonist pre-treatments every 48 h before an ischemic episode ameliorated ischemic brain damage in young ovariectomized or reproductively senescent (RS) aged female rats. The current study aims to investigate the efficacy of post-stroke ER-β agonist treatments in reducing ischemic brain damage and cognitive deficits in RS female rats. Retired breeder (9-10 months) Sprague-Dawley female rats were considered RS after remaining in constant diestrus phase for more than a month. The RS rats were exposed to transient middle cerebral artery occlusion (tMCAO) for 90 min and treated with either ER-β agonist (beta 2, 3-bis(4-hydroxyphenyl) propionitrile; DPN; 1 mg/kg; s.c.) or DMSO vehicle at 4.5 h after induction of tMCAO. Subsequently, rats were treated with either ER-β agonist or DMSO vehicle every 48 h for ten injections. Forty-eight hours after the last treatment, animals were tested for contextual fear conditioning to measure post-stroke cognitive outcome. Neurobehavioral testing, infarct volume quantification, and hippocampal neuronal survival were employed to determine severity of stroke. Periodic post-stroke ER-β agonist treatment reduced infarct volume, improved recovery of cognitive capacity by increasing freezing in contextual fear conditioning, and decreased hippocampal neuronal death in RS female rats. These data suggest that periodic post-stroke ER-β agonist treatment to reduce stroke severity and improve post-stroke cognitive outcome in menopausal women has potential for future clinical investigation., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chronic diabetes may cause secondary complications like stroke and also increase post-stroke brain damage. In stroke research, the Stroke Therapy Academic Industry Roundtable (STAIR) identified criteria to increase translational value of preclinical studies, which highlighted the importance of using animal models of comorbidities. Numerous animal models have been used to study the aggravation of ischemic brain damage in diabetics. In this chapter, we discuss rat and mouse models of streptozotocin (STZ)-induced diabetes, with an efficient method provided. We also provide an overview of spontaneously diabetic rodent models. We present different pathophysiological features of diabetes in each rodent model along with the advantages and disadvantages of each model. Utilizing these models may aid the advancement of novel treatments and therapies to lower ischemic brain damage in patients of diabetes., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Spontaneous intracerebral hemorrhage (sICH) is a deadly stroke subtype, and tobacco use increases sICH risk. However epidemiological studies show that, there are no confirmatory studies showing the effect of tobacco use on sICH outcome. Therefore, we evaluated the effect of chronic nicotine exposure (as a surrogate for tobacco use) on outcomes following sICH. Young male and female rats were randomly assigned to either nicotine (4.5 mg/kg b.w. per day) or vehicle (saline) treatment (2-3 weeks) groups. sICH was induced by injecting collagenase into the right striatum. Neurological score and hematoma volume were determined 24 h post-sICH. The hematoma volumes in nicotine-treated male and female rats were significantly higher by 42% and 48% when compared to vehicle-treated male and female rats, respectively. Neurological deficits measured in terms of neurological score for the nicotine-treated male and female groups were significantly higher when compared to the respective vehicle-treated male and female groups. Our results show that chronic nicotine exposure increases hematoma volume post-sICH in rats of both sexes. Identifying the mechanism of nicotine-dependent increase in hematoma growth post-sICH will be crucial to understanding the detrimental effect of tobacco use on the severity of bleeding following intracerebral hemorrhage.

This comprehensive review provides an insight into the pathophysiology, epidemiology, evaluation, and treatment of sickle cell anemia (SCA)-related stroke in developed and developing countries. Vascular injury, hypercoagulability and vaso-occlusion play a role in the pathophysiology of stroke in SCA. Transcranial Doppler ultrasound (TCD) has lowered the incidence of ischemic stroke from 11% to 1% as TCD identifies children who are at risk for stroke, providing opportunities for interventions to reduce this risk. Whereas blood exchange is indicated in acute stroke, chronic transfusions (either simple or exchange on a monthly basis) are used for primary as well as secondary stroke prevention in developed countries. Children with abnormally high TCD velocities (≥ 200 cm/s) are at high risk of stroke and might benefit from hydroxyurea or hydroxycarbamide (HU) after a period of a successful transition from chronic transfusions. Hematopoietic stem cell transplant presents a cure for SCA. Gene therapy is currently investigated and may be offered to patients with SCA who had a stroke or who are at high risk of stroke if proven efficacious and safe. However, gene therapy is not likely to be implemented in low-income countries due to cost. Alternatively, HU is utilized for primary and secondary stroke prevention in developing countries. Further expansion of TCD implementation should be a priority in those settings., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cerebral ischemia contributes to significant disabilities worldwide, impairing cognitive function and motor coordination in affected individuals. Stroke has severe neuropsychological outcomes, the major one being a stroke. Stroke survivors begin to show symptoms of depression within a few months of the incidence that overtime progresses to become a long-term ailment. As the pathophysiology for the progression of the disease is multifactorial and complex, it limits the understanding of the disease mechanism completely. Meta-analyses and randomized clinical trials have shown that intervening early with tricyclic antidepressants and selective serotonin receptor inhibitors can be effective. However, these pharmacotherapies possess several limitations that have given rise to newer approaches such as brain stimulation, psychotherapy and rehabilitation therapy, which in today's time are gaining attention for their beneficial results in post-stroke depression (PSD). The present review highlights numerous factors like lesion location, inflammatory mediators and genetic abnormalities that play a crucial role in the development of depression in stroke patients. Further, we have also discussed various mechanisms involved in post-stroke depression (PSD) and strategies for early detection and diagnosis using biomarkers that may revolutionize treatment for the affected population. Towards the end, along with the preclinical scenario, we have also discussed the various treatment approaches like pharmacotherapy, traditional medicines, psychotherapy, electrical stimulation and microRNAs being utilized for effectively managing PSD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Stroke is an event causing a disturbance in cerebral function leading to death and disability worldwide. Both acute kidney injury and chronic kidney disease (CKD) are associated with an increased risk of stroke and cerebrovascular events. The underlying mechanistic approach between impaired renal function and stroke is limitedly explored and has attracted researchers to learn more for developing therapeutic intervention. Common risk factors such as hypertension, hyperphosphatemia, atrial fibrillation, arteriosclerosis, hyperhomocysteinemia, blood-brain barrier disruption, inflammation, etc. are observed in the general population, but are high in renal failure patients. Also, risk factors like bone mineral metabolism, uremic toxins, and anemia, along with the process of dialysis in CKD patients, eventually increases the risk of stroke. Therefore, early detection of risks associated with stroke in CKD is imperative, which may decrease the mortality associated with it. This review highlights mechanisms by which kidney dysfunction can lead to cerebrovascular events and increase the risk of stroke in renal impairment., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Hemorrhagic transformation is a severe complication of acute ischemic stroke owing to its limited treatment options and poor prognosis. In the last decade, the rates of hemorrhagic transformation incidence have been associated with blood glucose levels. In particular, hyperglycemia at the time of admission has been associated with increased rates of hemorrhagic transformation in acute ischemic stroke patients. Recent pilot clinical trials have attempted to use intensive insulin therapy during stroke treatment to reduce the severity of cerebral infarction and possibly alleviate the risk of hemorrhagic transformation. However, the results of these studies have shown no clear clinical benefit. In addition, intensive insulin therapy has increased rates of hypoglycemia which may be associated with larger infarct growth. We hypothesize that hypoglycemia, similarly to hyperglycemia, is a risk factor for worse outcomes in acute ischemic stroke by promoting hemorrhagic transformation. This review serves to call attention to patterns present within intensive insulin therapy trials and shed light into the pathophysiological effects of hypoglycemia. It is critical that efforts be directed toward the prevention of hemorrhagic transformation by optimizing insulin therapy during the treatment of acute ischemic stroke.

Migraine and stroke are common, disabling neurological conditions with several theories being proposed to explain this bidirectional relationship. Migraine is considered as a benign neurological disorder, but research has revealed a connection between migraine and stroke, predominantly those having migraine with aura (MA). Among migraineurs, females with MA are more susceptible to ischemic stroke and may have a migrainous infarction. Migrainous infarction mostly occurs in the posterior circulation of young women. Although there are several theories about the potential relationship between MA and stroke, the precise pathological process of migrainous infarction is not clear. It is assumed that cortical spreading depression (CSD) might be one of the essential factors for migrainous infarction. Other factors that may contribute to migrainous infarction may be genetic, hormonal fluctuation, hypercoagulation, and right to left cardiac shunts. Antimigraine drugs, such as ergot alkaloids and triptans, are widely used in migraine care. Still, they have been found to cause severe vasoconstriction, which may result in the development of ischemia. It is reported that patients with stroke develop migraines during the recovery phase. Both experimental and clinical data suggest that cerebral microembolism can act as a potential trigger for MA. Further studies are warranted for the treatment of migraine, which may lead to a decline in migraine-related stroke. In this present article, we have outlined various potential pathways that link migraine and stroke.

Background Physical exercise and cognitive training have been recommended to improve cognitive outcomes poststroke, but a multifaceted strategy including aerobic, resistance, and cognitive training to facilitate poststroke recovery has not been investigated. We aimed to assess the feasibility, adherence, and safety of a combined aerobic, resistance, and cognitive training intervention (CARET+CTI) after stroke. Methods and Results We prospectively randomized patients presenting with recent stroke to a comparison of a supervised 12-week CARET+CTI program and a control group receiving sham CARET+CTI. Participants were scheduled for 3 weekly CARET and CTI sessions. All participants underwent pre- and postintervention assessments of strength, endurance, and cognition. The primary outcomes were feasibility and adherence, defined as the ratio of scheduled and observed visits, and safety. We enrolled 131 participants, of whom 37 withdrew from the study. There were 17 (20%) withdrawals in the CARET+CTI and 20 (44%) in the control group. The observed-over-expected visit ratio was significantly higher in the intervention than in the control group (0.74±0.30 versus 0.54±0.38; P =0.003). A total of 99 adverse events were reported by 59 participants, none of which were serious and related to the intervention. Greater gains in physical, cognitive, and mood outcomes were found in the CARET+CTI group than in the control group, but were not statistically significant after adjustments. Conclusions A CARET+CTI intervention, after stroke, is safe, feasible, and has satisfactory participant adherence over 12 weeks. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT02272426.

Background: The occurrence of secondary neurodegeneration has exclusively been observed after the first incidence of stroke. In humans and rodents, post-stroke secondary neurodegeneration (SND) is an inevitable event that can lead to progressive neuronal loss at a region distant to initial infarct. SND can lead to cognitive and motor function impairment, finally causing dementia. The exact pathophysiology of the event is yet to be explored. It is seen that the thalami, in particular, are susceptible to cause SND. The reason behind this is because the thalamus functioning as the relay center and is positioned as an interlocked structure with direct synaptic signaling connection with the cortex. As SND proceeds, accumulation of misfolded proteins and microglial activation are seen in the thalamus. This leads to increased neuronal loss and worsening of functional and cognitive impairment., Objective: There is a necessity of specific interventions to prevent post-stroke SND, which are not properly investigated to date owing to sparsely reproducible pre-clinical and clinical data. The basis of this review is to investigate about post-stroke SND and its updated treatment approaches carefully., Methods: Our article presents a detailed survey of advances in studies on stroke-induced secondary neurodegeneration (SND) and its treatment., Results: This article aims to put forward the pathophysiology of SND. We have also tabulated the latest treatment approaches along with different neuroimaging systems that will be helpful for future reference to explore., Conclusion: In this article, we have reviewed the available reports on SND pathophysiology, detection techniques, and possible treatment modalities that have not been attempted to date., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Inflammation is a devastating outcome of cerebrovascular diseases (CVD), namely stroke and atherosclerosis. Numerous studies over the decade have shown that inflammasomes play a role in mediating inflammatory reactions post cellular injury occurring after a stroke or a rupture of an atherosclerotic plaque. In view of this, targeting these inflammatory pathways using different pharmacological therapies may improve outcomes in patients with CVD. Here, we review the mechanisms by which inflammasomes drive the pathogenesis of stroke and atherosclerosis. Also, discussed here are the possible treatment strategies available for inhibiting inflammasomes or their up-stream/down-stream mediators., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: Calcineurin (CaN) is a threonine/phosphatase which play roles in neuronal homeostasis. Ischemic stroke induces hyperactivation of CaN which further triggers apoptotic signaling. CaN inhibition has limited therapeutic output and neurotoxicity due to its intricate roles in the neuronal network and requires a strategic modulation. Intra-arterial (IA) mesenchymal stem cells (MSCs) have shown to interact with the milieu in a paracrine manner as compared to CaN inhibitors to ameliorate the neuronal damage triggered by ischemia/reperfusion injury. The present study investigates the role of IA MSCs in modulating neuronal CaN after stroke onset. Materials and methods: To validate, middle-aged ovariectomized female rats exposed to MCAo (90 min) were treated with IA MSCs (1 × 10 5 MSCs) or phosphate-buffered saline (PBS) at 6 hours to check CaN expression in different groups.Tests for assessing functional and motor coordination were performed along with biochemical estimations. Furthermore, an inhibition study by non-selective inhibitor of neuronal calcium channel, flunarizine, was performed to explore the possible underlying mechanism by which IA MSCs may interact with CaN. Results: The study suggests that IA MSCs seemingly reduce the expression of CaN after ischemic stroke. IA MSCs have shown to improve the functional outcome and normalize oxidative parameters. Conclusion: Our study provides a preliminary evidence of role of IA MSCs in modulating CaN expression.

Ischemic stroke is devastating and a major cause of morbidity and mortality worldwide. To date, only clot retrieval devices and/or intravenous tissue plasminogen activators (tPA) have been approved by the US-FDA for the treatment of acute ischemic stroke. Therefore, there is an urgent need to develop an effective treatment for stroke that can have limited shortcomings and broad spectrum of applications. Interferon-beta (IFN-β), an endogenous cytokine and a key anti-inflammatory agent, contributes toward obviating deleterious stroke outcomes. Therefore, exploring the role of IFN-β may be a promising alternative approach for stroke intervention in the future. In the present review, we have discussed about IFN-β along with its different mechanistic roles in ischemic stroke. Furthermore, therapeutic approaches targeting the inflammatory cascade with IFN-β therapy that may be helpful in improving stroke outcome are also discussed., (© 2018 Wiley Periodicals, Inc.)

Aim: Stroke is devastating with a limited choice of intervention. Many pharmacological entities are available but none of them have evolved successfully in counteracting the multifaceted molecular alterations following stroke. Myeloperoxidase (MPO) has been reported to play an important role in neuroinflammation following neurodegenerative diseases. Therefore, using it as a therapeutic target may be a strategy to confer neuroprotection in stroke. Trigonelline (TG), a plant alkaloid has shown neuroprotective effects in the past. Here we explore its neuroprotective effects and its role in glutathione mediated MPO inhibition in ischemic stroke., Methods: An in silico study was performed to confirm effective TG and MPO interaction. An in vitro evaluation of toxicity with biochemical estimations was performed. Further, in vivo studies were undertaken where rats were treated with 25, 50 and 100 mg/kg TG or standard MPO inhibiting drug4‑Aminobenzoic hydrazide (4‑ABH) at 60 min prior, post immediate and an hour post 90 min of middle cerebral artery occlusion (MCAo) followed by 24 h reperfusion. Rats were evaluated for neurodeficit and motor function tests. Brains were further harvested for infarct size evaluation, biochemical analysis, and western blot experiments., Key Findings: TG at 100 mg/kg dose i.p. administered immediately post ischemia confers neuroprotection by reducing cerebral infarct with improvement in motor and neurodeficit scores. Furthermore, elevated nitrite and MDA levels were also found to be reduced in brain regions in the treated group. TG also potentiated intrinsic antioxidant status and markedly inhibited reduced glutathione mediated myeloperoxidase expression in the cortical brain region., Significance: TG confers neuroprotection by reduced glutathione mediated myeloperoxidase inhibition in ischemic stroke., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the treatment of both type 1 and type 2 diabetes mellitus, maintaining a euglycemic state represents one of the key challenges. Improper dosing and administration of glucose-lowering drugs is associated with an increased risk of recurrent hypoglycemia episodes. In addition, the risk of adverse cardiovascular events in diabetic patients, particularly myocardial infarctions and strokes, is well established. Current research indicates a potential link between the baseline risk of cardio/cerebrovascular events in diabetic patients and exposure to hypoglycemia. In this review of the literature, we aim to determine if a relationship exists between recurrent hypoglycemia and adverse neurovascular events., (© 2018 New York Academy of Sciences.)

Stroke is devastating and a major cause of morbidity and mortality around the world. The innate immune response plays an important role in various brain injuries, including stroke, and targeting it for therapeutic interventions would likely prove beneficial. The panoply of inflammatory cells, which induce various cellular, hormonal, and biochemical alterations, mediates the rapid progression of injury in stroke. The inflammasome, a multiprotein oligomer and a key component of specific innate immune responses, contributes toward the worsening of stroke outcomes by activating inflammatory cytokines. Acidotoxicity, mediated by acid-sensing ion channels (ASICs), also contributes toward exacerbating the condition. A role for ASICs in stroke, through the activation of the inflammasome, is emerging, which opens new avenues for understanding and intervening in stroke. In this review, we describe the various types of inflammasomes and their mechanisms of activation in stroke. Furthermore, therapeutic approaches targeting the inflammasome and that may be helpful in improving stroke outcome are discussed., (© 2018 New York Academy of Sciences.)

Stem cell therapy for ischemic stroke has widely been explored. Results from both preclinical and clinical studies have immensely supported the judicious use of stem cells as therapy. These provide an attractive means for preserving and replacing the damaged brain tissues following an ischemic attack. Since the past few years, researchers have used various types of stem cells to replenish insulted neuronal and glial cells in neurological disorders. In the present review, we discuss different types of stem cells employed for the treatment of ischemic stroke and mechanisms and challenges these cells face once introduced into the living system. Further, we also present different ways to maneuver and overcome challenges to translate the advances made at the preclinical level to clinics.

Stroke is devastating and a major cause of morbidity and mortality around globe. Current interventions for ischemic stroke include thrombolytics, clot retrieval devices and/or intravenous tissue plasminogen activators (tPA), the latter two becoming the first line of treatment. Owing to the limitations of tPA to elicit therapeutic benefits in a narrow time window, new pharmacological interventions are needed. Exploring noncoding RNAs (ncRNAs) may be a promising option for stroke treatment. ncRNAs are endogenous molecules that play key roles in the pathophysiology of many functions and diseases, including during ischemic stroke. Small ncRNAs such as microRNAs, Piwi-interacting RNAs, and long ncRNAs affect the genetic machinery at molecular levels. These small ncRNAs, along with their target genes and RNA transcripts, are involved in repair and recovery mechanisms after stroke. The potential of ncRNAs to regulate physiological processes highlights their potential therapeutic importance. Here, we enumerate the details and roles of different types of ncRNAs as biomarkers and targets for future stroke intervention., (© 2018 New York Academy of Sciences.)

Numerous preclinical studies have been carried out using mesenchymal stem cells (MSCs) therapy for ischemic stroke. The purpose of the present meta-analysis is to review the quality of preclinical studies. In all, 4,361 articles were identified, out of which 64 studies were included (excluding in vitro studies). The results were obtained across species, route, and time of administration, immunogenicity, and doses. The median quality score 4.90/10, confidence interval 95%, and large effect size were observed, which strongly supports the translation potential of MSC therapy for ischemic stroke., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Background and Purpose: Resveratrol, at least in part via SIRT1 (silent information regulator 2 homologue 1) activation, protects against cerebral ischemia when administered 2 days before injury. However, it remains unclear if SIRT1 activation must occur, and in which brain cell types, for the induction of neuroprotection. We hypothesized that neuronal SIRT1 is essential for resveratrol-induced ischemic tolerance and sought to characterize the metabolic pathways regulated by neuronal Sirt1 at the cellular level in the brain., Methods: We assessed infarct size and functional outcome after transient 60 minute middle cerebral artery occlusion in control and inducible, neuronal-specific SIRT1 knockout mice. Nontargeted primary metabolomics analysis identified putative SIRT1-regulated pathways in brain. Glycolytic function was evaluated in acute brain slices from adult mice and primary neuronal-enriched cultures under ischemic penumbra-like conditions., Results: Resveratrol-induced neuroprotection from stroke was lost in neuronal Sirt1 knockout mice. Metabolomics analysis revealed alterations in glucose metabolism on deletion of neuronal Sirt1 , accompanied by transcriptional changes in glucose metabolism machinery. Furthermore, glycolytic ATP production was impaired in acute brain slices from neuronal Sirt1 knockout mice. Conversely, resveratrol increased glycolytic rate in a SIRT1-dependent manner and under ischemic penumbra-like conditions in vitro., Conclusions: Our data demonstrate that resveratrol requires neuronal SIRT1 to elicit ischemic tolerance and identify a novel role for SIRT1 in the regulation of glycolytic function in brain. Identification of robust neuroprotective mechanisms that underlie ischemia tolerance and the metabolic adaptations mediated by SIRT1 in brain are crucial for the translation of therapies in cerebral ischemia and other neurological disorders., (© 2017 American Heart Association, Inc.)

Cerebral ischemia in diabetics results in severe brain damage. Different animal models of cerebral ischemia have been used to study the aggravation of ischemic brain damage in the diabetic condition. Since different disease conditions such as diabetes differently affect outcome following cerebral ischemia, the Stroke Therapy Academic Industry Roundtable (STAIR) guidelines recommends use of diseased animals for evaluating neuroprotective therapies targeted to reduce cerebral ischemic damage. The goal of this review is to discuss the technicalities and pros/cons of various animal models of cerebral ischemia currently being employed to study diabetes-related ischemic brain damage. The rational use of such animal systems in studying the disease condition may better help evaluate novel therapeutic approaches for diabetes related exacerbation of ischemic brain damage., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Stroke is one of the leading causes of death worldwide. A strong inflammatory response characterized by activation and release of cytokines, chemokines, adhesion molecules, and proteolytic enzymes contributes to brain damage following stroke. Stroke outcomes are worse among diabetics, resulting in increased mortality and disabilities. Diabetes involves chronic inflammation manifested by reactive oxygen species generation, expression of proinflammatory cytokines, and activation/expression of other inflammatory mediators. It appears that increased proinflammatory processes due to diabetes are further accelerated after cerebral ischemia, leading to increased ischemic damage. Hypoglycemia is an intrinsic side effect owing to glucose-lowering therapy in diabetics, and is known to induce proinflammatory changes as well as exacerbate cerebral damage in experimental stroke. Here, we present a review of available literature on the contribution of neuroinflammation to increased cerebral ischemic damage in diabetics. We also describe the role of hypoglycemia in neuroinflammation and cerebral ischemic damage in diabetics. Understanding the role of neuroinflammatory mechanisms in worsening stroke outcome in diabetics may help limit ischemic brain injury and improve clinical outcomes.

Ischemic preconditioning is an innate neuroprotective mechanism in which a sub-injurious ischemic exposure increases the brain's ability to withstand a subsequent, normally injurious ischemic insult. Part of ischemic preconditioning neuroprotection stems from an epigenetic reprogramming of the brain to a phenotype of ischemic tolerance, which results in a gene expression profile different from that observed in the non-injured and ischemia-injured brains. Such neuroprotective reprograming, activated by ischemic preconditioning, requires specific changes in DNA accessibility coordinated with activation of transcriptional activator and repressor proteins, which allows for expression of specific neuroprotective proteins despite a general repression of gene expression. In this review we examine the effects of injurious ischemia and ischemic preconditioning on the regulation of DNA methylation, histone post-translational modifications, and non-coding RNA expression. There is increasing interest in the role of epigenetics in disease pathobiology, and whether and how pharmacological manipulation of epigenetic processes may allow for ischemic neuroprotection. Therefore, a better understanding of the epigenomic determinants underlying the modulation of gene expression that lead to ischemic tolerance or cell death offers the promise of novel neuroprotective therapies that target global reprograming of genomic activity versus individual cellular signaling pathways.

Background: Several studies suggest transient ischemic attack (TIA) may be neuroprotective against ischemic stroke analogous to preinfarction angina's protection against acute myocardial infarction. However, this protective ischemic preconditioning-like effect may not be present in all ages, especially among the elderly. The purpose of this study was to determine the neuroprotective effect of TIAs (clinical equivalent of cerebral ischemic preconditioning) to neurologic damage after cerebral ischemic injury in patients over 65 years of age., Methods: We reviewed the medical charts of patients with ischemic stroke for presence of TIAs within 72 hours before stroke onset. Stroke severity was evaluated by the National Institutes of Health Stroke Scale and disability by a modified Rankin scale., Results: We evaluated 203 patients (>or=65 years) with diagnosis of acute ischemic stroke and categorized them according to the presence (n = 42, 21%) or absence (n = 161, 79%) of TIAs within 72 hours of stroke onset. Patients were monitored until discharged from the hospital (length of hospital stay 14.5 +/- 4.8 days). No significant differences in the National Institutes of Health Stroke Scale and modified Rankin scale scores were observed between those patients with TIAs and those without TIAs present before stroke onset at admission or discharge., Conclusion: These results suggest that the neuroprotective mechanism of cerebral ischemic preconditioning may not be present or functional in the elderly.

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.

Smoking-derived nicotine (N) and oral contraceptive (OC) synergistically exacerbate ischemic brain damage in females, and the underlying mechanisms remain elusive. In a previous study, we showed that N + OC exposure altered brain glucose metabolism in females. Since lipid metabolism complements glycolysis, the current study aims to examine the metabolic fingerprint of fatty acids in the brain of female rats exposed to N+/−OC. Adolescent and adult Sprague–Dawley female rats were randomly (n = 8 per group) exposed to either saline or N (4.5 mg/kg) +/−OC (combined OC or placebo delivered via oral gavage) for 16–21 days. Following exposure, brain tissue was harvested for unbiased metabolomic analysis (performed by Metabolon Inc., Morrisville, NC, USA) and the metabolomic profile changes were complemented with Western blot analysis of key enzymes in the lipid pathway. Metabolomic data showed significant accumulation of fatty acids and phosphatidylcholine (PC) metabolites in the brain. Adolescent, more so than adult females, exposed to N + OC showed significant increases in carnitine-conjugated fatty acid metabolites compared to saline control animals. These changes in fatty acyl carnitines were accompanied by an increase in a subset of free fatty acids, suggesting elevated fatty acid β-oxidation in the mitochondria to meet energy demand. In support, β-hydroxybutyrate was significantly lower in N + OC exposure groups in adolescent animals, implying a complete shunting of acetyl CoA for energy production via the TCA cycle. The reported changes in fatty acids and PC metabolism due to N + OC could inhibit post-translational palmitoylation of membrane proteins and synaptic vesicle formation, respectively, thus exacerbating ischemic brain damage in female rats. [ABSTRACT FROM AUTHOR]

Spontaneous intracerebral hemorrhage (sICH) is a disabling stroke sub-type, and tobacco use is a prominent risk factor for sICH. We showed that chronic nicotine exposure enhances bleeding post-sICH. Reduction of hematoma growth is a promising effective therapy for sICH in smoking subjects. Red-blood-cell-derived microparticles (RMPs) are hemostatic agents that limit hematoma expansion following sICH in naïve rats. Considering the importance of testing the efficacy of experimental drugs in animal models with a risk factor for a disease, we tested RMP efficacy and the therapeutic time window in limiting hematoma growth post-sICH in rats exposed to nicotine. Young rats were chronically treated with nicotine using osmotic pumps. sICH was induced in rats using an injection of collagenase in the right striatum. Vehicle/RMPs were administered intravenously. Hematoma volume and neurological impairment were quantified ≈24 h after sICH. Hematoma volumes in male and female nicotine-exposed rats that were treated with RMPs at 2 h post-sICH were significantly lower by 26 and 31% when compared to their respective control groups. RMP therapy was able to limit hematoma volume when administered up to 4.5 h post-sICH in animals of both sexes. Therefore, RMPs may limit hematoma growth in sICH patients exposed to tobacco use. [ABSTRACT FROM AUTHOR]

Stroke remains a leading cause of death and disability in the United States. No current treatments exist to promote cognitive recovery in survivors of stroke. A previous study from our laboratory determined that an acute bout of forced treadmill exercise was able to promote cognitive recovery in 3 month old male rats after middle cerebral artery occlusion (MCAo). In this study, we tested the hypothesis that 6 days of intense acute bout of forced treadmill exercise (physical exercise – PE) promotes cognitive recovery in 11–14 month old male rats. We determined that PE was able to ameliorate cognitive deficits as determined by contextual fear conditioning. Additionally, we also tested the hypothesis that PE promotes cognitive recovery in 11–13 month old reproductive senescent female rats. In contrast to males, the same intensity of exercise that decrease cognitive deficits in males was not able to promote cognitive recovery in female rats. Additionally, we determined that exercise did not lessen infarct volume in both male and female rats. There are many factors that contribute to higher stroke mortality and morbidities in women and thus, future studies will investigate the effects of PE in aged female rats to identify sex differences. [ABSTRACT FROM AUTHOR]

Stroke is among the leading causes of mortality and morbidity worldwide. Stroke incidences and associated mortality are expected to rise to 23 million and 7.8 million, respectively, by 2030. Further, the aging population, imbalanced lifestyles, and environmental factors continue to shift the rate of stroke incidence, particularly in developing countries. There is an urgent need to develop new therapeutic approaches for treating stroke. Nanotechnology is a growing field, offering an encouraging future prospect for medical research in the management of strokes. The world market for nanotechnology derived products is expected to rise manyfold in the coming decades. Different types of nanomaterials such as perfluorocarbon nanoparticles, iron oxide nanoparticles, gold nanoparticles, polymeric nanoparticles, quantum dots, nanospheres, etc. have been developed for the diagnosis as well as therapy of strokes. Today, nanotechnology has also been integrated with stem cell therapy for treating stroke. However several obstacles remain to be overcome when using such nanomaterials for treating stroke and other neurological diseases. [ABSTRACT FROM AUTHOR]

Cerebral ischemia affects millions of people worldwide and survivors suffer from long-term functional and cognitive deficits. While stroke and cardiac arrest are typically considered when discussing ischemic brain injuries, there is much evidence that smaller ischemic insults underlie neurodegenerative diseases, including Alzheimer's disease. The "regenerative" capacity of the brain relies on several aspects of plasticity that are crucial for normal functioning; less affected brain areas may take over function previously performed by irreversibly damaged tissue. To harness the endogenous plasticity mechanisms of the brain to provide recovery of cognitive function, we must first understand how these mechanisms are altered after damage, such as cerebral ischemia. In this review, we discuss the long-term cognitive changes that result after cerebral ischemia and how ischemia alters several plasticity processes. We conclude with a discussion of how current and prospective therapies may restore brain plasticity and allow for recovery of cognitive function, which may be applicable to several disorders that have a disruption of cognitive processing, including traumatic brain injury and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract: Mammals that hibernate experience extreme metabolic states and body temperatures as they transition between euthermia, a state resembling typical warm blooded mammals, and prolonged torpor, a state of suspended animation where the brain receives as low as 10% of normal cerebral blood flow. Transitions into and out of torpor are more physiologically challenging than the extreme metabolic suppression and cold body temperatures of torpor per se. Mammals that hibernate show unprecedented capacities to tolerate cerebral ischemia, a decrease in blood flow to the brain caused by stroke, cardiac arrest or brain trauma. While cerebral ischemia often leads to death or disability in humans and most other mammals, hibernating mammals suffer no ill effects when blood flow to the brain is dramatically decreased during torpor or experimentally induced during euthermia. These animals, as adults, also display rapid and pronounced synaptic flexibility where synapses retract during torpor and rapidly re-emerge upon arousal. A variety of coordinated adaptations contribute to tolerance of cerebral ischemia in these animals. In this review we discuss adaptations in heterothermic mammals that may suggest novel therapeutic targets and strategies to protect the human brain against cerebral ischemic damage and neurodegenerative disease. [Copyright &y& Elsevier]

Abstract: More than 65% of mortality among diabetics is due to stroke and heart disease. The major side effect of intensive therapy in both type 1 and type 2 diabetics is recurrent hypoglycemic episodes (RH). Our previous study in a rat model of insulin-requiring diabetes indicated that RH exacerbates cerebral ischemic damage. Studies related to RH in hypoglycemia unawareness suggest that RH may be deleterious to outcome following cerebral ischemia owing to systemic effects, since hormonal response to hypoglycemia is impaired following RH. The goal of the present study was to determine if RH increases oxygen-glucose deprivation (OGD)-induced damage in hippocampal organotypic slices, which are devoid of systemic influence. Hippocampal slices cultured in ex vivo conditions for 9–10 days were exposed to ten 30-min episodes of “hypoglucose” (to mimic the hypoglycemic condition) medium (1.06mM) twice a day. Slices were exposed to OGD 12h after the last hypo/normo-glucose exposure. OGD in control slices resulted in 60% neuronal death. The percentage of cell death in RH-treated slices was significantly higher by 24% than in control slices. The results demonstrate that RH can affect brain cells in the absence of humoral influence. In conclusion, the previous exposure of hippocampal slices to RH exacerbates OGD-induced damage. Understanding the mechanism by which RH increases ischemic damage in diabetics will help improve outcome following stroke. [Copyright &y& Elsevier]

Abstract: Ischemic preconditioning (IPC) is a phenomenon whereby an organ''s adaptive transient resistance to a lethal ischemic insult occurs by preconditioning this organ with a sub-lethal/mild ischemic insult of short duration. Besides IPC, recent studies reported that a short sub-lethal ischemia and reperfusion in various organs can induce ischemic tolerance in another organ as well. This phenomenon is known as remote ischemic preconditioning (RPC). In the present study we tested the hypothesis that tolerance for ischemia can be induced in brain by RPC and IPC in a rat model of asphyxial cardiac arrest (ACA). RPC was induced by tightening the upper two-thirds of both hind limbs using a tourniquet for 15 or 30min and IPC was induced by tightening bilateral carotid artery ligatures for 2min. Eight minutes of ACA was induced 48h after RPC or IPC. After 7 day of resuscitation, brains were extracted and examined for histopathological changes. In CA1 hippocampus, the number of normal neurons was 63% lower in cardiac-arrested rats as compared to the control group. The number of normal neurons in the 15min RPC, 30min RPC, and IPC groups was higher than the ACA group by 54, 70, and 67%, respectively. This study demonstrates that RPC and IPC are able to provide neuroprotection in a rat model of ACA. Besides direct application of RPC or IPC paradigms, the exploration of the mechanisms of observed neuroprotection by RPC and IPC may also lead to a possible therapy for CA patients. [Copyright &y& Elsevier]