Resveratrol Preconditioning Mitigates Ischemia-Induced Septal Cholinergic Cell Loss and Memory Impairments.

BACKGROUND: Cholinergic cells originating from the nuclei of the basal forebrain (BF) are critical for supporting various memory processes, yet BF cholinergic cell viability has not been explored in the context of focal cerebral ischemia. In the present study, we examined cell survival within several BF nuclei in rodents following transient middle cerebral artery occlusion. We tested the hypothesis that a previously established neuroprotective therapy-resveratrol preconditioning-would rescue BF cell loss, deficits in cholinergic-related memory performance, and hippocampal synaptic dysfunction after focal cerebral ischemia. METHODS: Adult (2-3-month old) male Sprague-Dawley rats or wild-type C57Bl/6J mice were injected intraperitoneally with a single dose of resveratrol or vehicle and subjected to transient middle cerebral artery occlusion using the intraluminal suture method 2 days later. Histopathological, behavioral, and electrophysiological outcomes were measured 1-week post-reperfusion. Animals with reduction in cerebral blood flow <30% of baseline were excluded. RESULTS: Cholinergic cell loss was observed in the medial septal nucleus and diagonal band of Broca following transient middle cerebral artery occlusion. This effect was prevented by resveratrol preconditioning, which also ameliorated transient middle cerebral artery occlusion-induced deficits in cognitive performance and hippocampal long-term potentiation. CONCLUSIONS: We demonstrate for the first time that focal cerebral ischemia induces cholinergic cell death within memory-relevant nuclei of the BF. The preservation of cholinergic cell viability may provide a mechanism by which resveratrol preconditioning improves memory performance and preserves functionality of memory-processing brain structures after focal cerebral ischemia.

Red Blood Cell Microparticles Limit Hematoma Growth in Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (sICH) is the deadliest stroke subtype with no effective therapies. Limiting hematoma expansion is a promising therapeutic approach. Red blood cell-derived microparticles (RMPs) are novel hemostatic agents. Therefore, we studied the potential of RMPs in limiting hematoma growth and improving outcomes post-sICH. METHODS: sICH was induced in rats by intrastriatal injection of collagenase. RMPs were prepared from human RBCs by high-pressure extrusion. Behavioral and hematoma/lesion volume assessment were done post-sICH. The optimal dose, dosing regimen, and therapeutic time window of RMP therapy required to limit hematoma growth post-sICH were determined. We also evaluated the effect of RMPs on long-term behavioral and histopathologic outcomes post-sICH. RESULTS: RMP treatment limited hematoma growth following sICH. Hematoma volume (mm3) for vehicle- and RMP- (2.66×1010 particles/kg) treated group was 143±8 and 86±4, respectively. The optimal RMP dosing regimen that limits hematoma expansion was identified. RMPs limit hematoma volume when administered up to 4.5-hour post-sICH. Hematoma volume in the 4.5-hour post-sICH RMP treatment group was lower by 24% when compared with the control group. RMP treatment also improved long-term histopathologic and behavioral outcomes post-sICH. CONCLUSIONS: Our results demonstrate that RMP therapy limits hematoma growth and improves outcomes post-sICH in a rodent model. Therefore, RMPs have the potential to limit hematoma growth in sICH patients.

The Impact of Nicotine along with Oral Contraceptive Exposure on Brain Fatty Acid Metabolism in Female Rats.

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 ß-oxidation in the mitochondria to meet energy demand. In support, ß-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.

Red Cell Microparticles Suppress Hematoma Growth Following Intracerebral Hemorrhage in Chronic Nicotine-Exposed Rats.

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.

Neuroimmune crosstalk and evolving pharmacotherapies in neurodegenerative diseases.

Neurodegeneration is characterized by gradual onset and limited availability of specific biomarkers. Apart from various aetiologies such as infection, trauma, genetic mutation, the interaction between the immune system and CNS is widely associated with neuronal damage in neurodegenerative diseases. The immune system plays a distinct role in disease progression and cellular homeostasis. It induces cellular and humoral responses, and enables tissue repair, cellular healing and clearance of cellular detritus. Aberrant and chronic activation of the immune system can damage healthy neurons. The pro-inflammatory mediators secreted by chief innate immune components, the complement system, microglia and inflammasome can augment cytotoxicity. Furthermore, these inflammatory mediators accelerate microglial activation resulting in progressive neuronal loss. Various animal studies have been carried out to unravel the complex pathology and ascertain biomarkers for these harmful diseases, but have had limited success. The present review will provide a thorough understanding of microglial activation, complement system and inflammasome generation, which lead the healthy brain towards neurodegeneration. In addition to this, possible targets of immune components to confer a strategic treatment regime for the alleviation of neuronal damage are also summarized.

Cerebro-renal interaction and stroke.

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.

Therapeutic spectrum of interferon-ß in ischemic stroke.

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-ß), an endogenous cytokine and a key anti-inflammatory agent, contributes toward obviating deleterious stroke outcomes. Therefore, exploring the role of IFN-ß may be a promising alternative approach for stroke intervention in the future. In the present review, we have discussed about IFN-ß along with its different mechanistic roles in ischemic stroke. Furthermore, therapeutic approaches targeting the inflammatory cascade with IFN-ß therapy that may be helpful in improving stroke outcome are also discussed.

Intra-arterial stem cell therapy modulates neuronal calcineurin and confers neuroprotection after ischemic stroke.

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 × 105 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.

Age-Dependent Levels of Protein Kinase Cs in Brain: Reduction of Endogenous Mechanisms of Neuroprotection.

Neurodegenerative diseases are among the leading causes of mortality and disability worldwide. However, current therapeutic approaches have failed to reach significant results in their prevention and cure. Protein Kinase Cs (PKCs) are kinases involved in the pathophysiology of neurodegenerative diseases, such as Alzheimer's Disease (AD) and cerebral ischemia. Specifically ε, δ, and γPKC are associated with the endogenous mechanism of protection referred to as ischemic preconditioning (IPC). Existing modulators of PKCs, in particular of εPKC, such as ψεReceptor for Activated C-Kinase (ψεRACK) and Resveratrol, have been proposed as a potential therapeutic strategy for cerebrovascular and cognitive diseases. PKCs change in expression during aging, which likely suggests their association with IPC-induced reduction against ischemia and increase of neuronal loss occurring in senescent brain. This review describes the link between PKCs and cerebrovascular and cognitive disorders, and proposes PKCs modulators as innovative candidates for their treatment. We report original data showing εPKC reduction in levels and activity in the hippocampus of old compared to young rats and a reduction in the levels of δPKC and γPKC in old hippocampus, without a change in their activity. These data, integrated with other findings discussed in this review, demonstrate that PKCs modulators may have potential to restore age-related reduction of endogenous mechanisms of protection against neurodegeneration.

Neuronal SIRT1 (Silent Information Regulator 2 Homologue 1) Regulates Glycolysis and Mediates Resveratrol-Induced Ischemic Tolerance.

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.

Physical Exercise Improves Cognitive Outcomes in 2 Models of Transient Cerebral Ischemia.

BACKGROUND AND PURPOSE: Preclinical studies suggest that exercise can enhance cognition after cerebral ischemia but often use long training regiments and test cognition during or acutely after training. The cognitive changes may result from enhanced physical fitness and may only provide acute benefit. We sought to determine whether a short period of exercise after cerebral ischemia could improve cognitive outcomes when measured days after completion of exercise training in 2 cerebral ischemia models. METHODS: Focal or global cerebral ischemia was induced in Sprague-Dawley rats. Rats recovered (3-4 days) then were subject to no exercise (0 m/min), mild (6 m/min), moderate (10 m/min), or heavy (15-18 m/min) treadmill exercise (5-6 days). Cognition was tested 8 to 10 days after the last exercise session with hippocampal-dependent contextual fear conditioning. RESULTS: A short training period of moderate exercise enhanced cognitive function for a week after exercise completion in both models of cerebral ischemia. CONCLUSIONS: Utilization of this exercise paradigm can further the elucidation of exercise-mediated factors involved in cognitive recovery independent of changes in physical fitness.

Cerebral ischemic damage in diabetes: an inflammatory perspective.

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.

Resveratrol Preconditioning Protects Against Cerebral Ischemic Injury via Nuclear Erythroid 2-Related Factor 2.

BACKGROUND AND PURPOSE: Nuclear erythroid 2 related factor 2 (Nrf2) is an astrocyte-enriched transcription factor that has previously been shown to upregulate cellular antioxidant systems in response to ischemia. Although resveratrol preconditioning (RPC) has emerged as a potential neuroprotective therapy, the involvement of Nrf2 in RPC-induced neuroprotection and mitochondrial reactive oxygen species production after cerebral ischemia remains unclear. The goal of our study was to study the contribution of Nrf2 to RPC and its effects on mitochondrial function. METHODS: We used rodent astrocyte cultures and an in vivo stroke model with RPC. An Nrf2 DNA binding ELISA and protein analysis via Western blotting of downstream Nrf2 targets were performed to determine RPC-induced activation of Nrf2 in rat and mouse astrocytes. After RPC, mitochondrial function was determined by measuring reactive oxygen species production and mitochondrial respiration in both wild-type and Nrf2-/- mice. Infarct volume was measured to determine neuroprotection, whereas protein levels were measured by immunoblotting. RESULTS: We report that Nrf2 is activated by RPC in rodent astrocyte cultures, and that loss of Nrf2 reduced RPC-mediated neuroprotection in a mouse model of focal cerebral ischemia. In addition, we observed that wild-type and Nrf2-/- cortical mitochondria exhibited increased uncoupling and reactive oxygen species production after RPC treatments. Finally, Nrf2-/- astrocytes exhibited decreased mitochondrial antioxidant expression and were unable to upregulate cellular antioxidants after RPC treatment. CONCLUSIONS: Nrf2 contributes to RPC-induced neuroprotection through maintaining mitochondrial coupling and antioxidant protein expression.

Resveratrol Preconditioning Induces a Novel Extended Window of Ischemic Tolerance in the Mouse Brain.

BACKGROUND AND PURPOSE: Prophylactic treatments that afford neuroprotection against stroke may emerge from the field of preconditioning. Resveratrol mimics ischemic preconditioning, reducing ischemic brain injury when administered 2 days before global ischemia in rats. This protection is linked to silent information regulator 2 homologue 1 (Sirt1) and enhanced mitochondrial function possibly through its repression of uncoupling protein 2. Brain-derived neurotrophic factor (BDNF) is another neuroprotective protein associated with Sirt1. In this study, we sought to identify the conditions of resveratrol preconditioning (RPC) that most robustly induce neuroprotection against focal ischemia in mice. METHODS: We tested 4 different RPC paradigms against a middle cerebral artery occlusion model of stroke. Infarct volume and neurological score were calculated 24 hours after middle cerebral artery occlusion. Sirt1-chromatin binding was evaluated by ChIP-qPCR. Percoll gradients were used to isolate synaptic fractions, and changes in protein expression were determined via Western blot analysis. BDNF concentration was measured using a BDNF-specific ELISA assay. RESULTS: Although repetitive RPC induced neuroprotection from middle cerebral artery occlusion, strikingly one application of RPC 14 days before middle cerebral artery occlusion showed the most robust protection, reducing infarct volume by 33% and improving neurological score by 28%. Fourteen days after RPC, Sirt1 protein was increased 1.5-fold and differentially bound to the uncoupling protein 2 and BDNF promoter regions. Accordingly, synaptic uncoupling protein 2 level decreased by 23% and cortical BDNF concentration increased 26%. CONCLUSIONS: RPC induces a novel extended window of ischemic tolerance in the brain that lasts for at least 14 days. Our data suggest that this tolerance may be mediated by Sirt1 through upregulation of BDNF and downregulation of uncoupling protein 2.

Signaling pathways leading to ischemic mitochondrial neuroprotection.

There is extensive evidence that ischemic/reperfusion mediated mitochondrial dysfunction is a major contributor to ischemic damage. However data also indicates that mild ischemic stress induces mitochondrial dependent activation of ischemic preconditioning. Ischemic preconditioning is a neuroprotective mechanism which is activated upon a brief sub-injurious ischemic exposure and is sufficient to provide protection against a subsequent lethal ischemic insult. Current research demonstrates that mitochondria are not only the inducers of but are also an important target of ischemic preconditioning mediated protection. Numerous proteins and signaling pathways are activated by ischemic preconditioning which protect the mitochondria against ischemic damage. In this review we examine some of the proteins activated by ischemic precondition which counteracts the deleterious effects of ischemia/reperfusion thereby maintaining normal mitochondrial activity and lead to ischemic tolerance.

Hyperglycemia / hypoglycemia-induced mitochondrial dysfunction and cerebral ischemic damage in diabetics.

Enhancement of ischemic brain damage is one of the most serious complications of diabetes. Studies from various in vivo and in vitro models of cerebral ischemia have led to an understanding of the role of mitochondria and complex interrelated mitochondrial biochemical pathways leading to the aggravation of ischemic neuronal damage. Advancements in the elucidation of the mechanisms of ischemic brain damage in diabetic subjects have revealed a number of key mitochondrial targets that have been hypothesized to participate in enhancement of brain damage. The present review initially discusses the neurobiology of ischemic neuronal injury, with special emphasis on the central role of mitochondria in mediating its pathogenesis and therapeutic targets. Later it further details the potential role of various biochemical mediators and second messengers causing widespread ischemic brain damage among diabetics via mitochondrial pathways. The present review discusses preclinical data which validates the significance of mitochondrial mechanisms in mediating the aggravation of ischemic cerebral injury in diabetes. Exploitation of these targets may provide effective therapeutic agents for the management of diabetes-related aggravation of ischemic neuronal damage.

The role of deimination in ATP5b mRNA transport in a transgenic mouse model of multiple sclerosis.

Deimination refers to conversion of protein-bound arginine into citrulline. An mRNA carrier, RNA binding export factor (REF), present on mitochondria undergoes loss of deimination with impaired ATP5b mRNA transport in ND4 mice (model of multiple sclerosis) compared with the controls. We present evidence of (1) reduced ATP5b mRNA binding strength of non-deiminated REF compared with deiminated REF, (2) impaired ATP5b mRNA transport in ND4 mice and (3) reduced mitochondrial ATP synthase activity on inhibition of deimination in PC12 cells. Impaired deimination of REF and defect in mitochondrial mRNA transport are critical factors in mitochondrial dysfunction in ND4 mice.

Resveratrol Preconditioning Downregulates PARP1 Protein to Alleviate PARP1-Mediated Cell Death Following Cerebral Ischemia.

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.

Ischemic preconditioning and clinical scenarios.

PURPOSE OF REVIEW: Ischemic preconditioning (IPC) is gaining attention as a novel neuroprotective therapy and could provide an improved mechanistic understanding of tolerance to cerebral ischemia. The purpose of this article is to review the recent work in the field of IPC and its applications to clinical scenarios. RECENT FINDINGS: The cellular signaling pathways that are activated following IPC are now better understood and have enabled investigators to identify several IPC mimetics. Most of these studies were performed in rodents, and efficacy of these mimetics remains to be evaluated in human patients. Additionally, remote ischemic preconditioning (RIPC) may have higher translational value than IPC. Repeated cycles of temporary ischemia in a remote organ can activate protective pathways in the target organ, including the heart and brain. Clinical trials are underway to test the efficacy of RIPC in protecting brain against subarachnoid hemorrhage. SUMMARY: IPC, RIPC, and IPC mimetics have the potential to be therapeutic in various clinical scenarios. Further understanding of IPC-induced neuroprotection pathways and utilization of clinically relevant animal models are necessary to increase the translational potential of IPC in the near future.