Reactive astrocytes prevent maladaptive plasticity after ischemic stroke

Restoration of functional connectivity is a major contributor to functional recovery after stroke. We investigated the role of reactive astrocytes in functional connectivity and recovery after photothrombotic stroke in mice with attenuated reactive gliosis (GFAP−/−Vim−/−). Infarct volume and longitudinal functional connectivity changes were determined by in vivo T2-weighted MRI and resting-state functional MRI. Sensorimotor function was assessed with behavioral tests, and glial and neural plasticity responses were quantified in the peri-infarct region. Four weeks after stroke, GFAP−/−Vim−/− mice showed impaired recovery of sensorimotor function and aberrant restoration of global neuronal connectivity. These mice also exhibited maladaptive plasticity responses, shown by higher number of lost and newly formed functional connections between primary and secondary targets of cortical stroke regions and increased peri-infarct expression of the axonal plasticity marker Gap43. We conclude that reactive astrocytes are required for optimal recovery-promoting plasticity responses after ischemic stroke.

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Non-Invasive Multimodality Imaging Directly Shows TRPM4 Inhibition Ameliorates Stroke Reperfusion Injury

Translational Stroke Research ◽

10.1007/s12975-018-0621-3 ◽

2018 ◽

Vol 10 (1) ◽

pp. 91-103 ◽

Cited By ~ 12

Author(s):

Bo Chen ◽

Gandi Ng ◽

Yahui Gao ◽

See Wee Low ◽

Edwin Sandanaraj ◽

...

Keyword(s):

Ischemic Stroke ◽

Transient Receptor Potential ◽

Multimodality Imaging ◽

Infarct Volume ◽

Triphenyltetrazolium Chloride ◽

In Vivo Evaluation ◽

Transient Receptor Potential Melastatin ◽

Imaging Results ◽

Trpm4 Channel

Abstract The transient receptor potential melastatin 4 (TRPM4) channel has been suggested to play a key role in the treatment of ischemic stroke. However, in vivo evaluation of TRPM4 channel, in particular by direct channel suppression, is lacking. In this study, we used multimodal imaging to assess edema formation and quantify the amount of metabolically functional brain salvaged after a rat model of stroke reperfusion. TRPM4 upregulation in endothelium emerges as early as 2 h post-stroke induction. Expression of TRPM4 channel was suppressed directly in vivo by treatment with siRNA; scrambled siRNA was used as a control. T2-weighted MRI suggests that TRPM4 inhibition successfully reduces edema by 30% and concomitantly salvages functionally active brain, measured by 18F-FDG-PET. These in vivo imaging results correlate well with post-mortem 2,3,5-triphenyltetrazolium chloride (TTC) staining which exhibits a 34.9% reduction in infarct volume after siRNA treatment. Furthermore, in a permanent stroke model, large areas of brain tissue displayed both edema and significant reductions in metabolic activity which was not shown in transient models with or without TRPM4 inhibition, indicating that tissue salvaged by TRPM4 inhibition during stroke reperfusion may survive. Evans Blue extravasation and hemoglobin quantification in the ipsilateral hemisphere were greatly reduced, suggesting that TRPM4 inhibition can improve BBB integrity after ischemic stroke reperfusion. Our results support the use of TRPM4 blocker for early stroke reperfusion.

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Abstract WMP76: Interleukin-33 Protects Against Transient Ischemic Stroke by Enhancing Regulatory T-Cell Expansion and Accumulation

Stroke ◽

10.1161/str.51.suppl_1.wmp76 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Xinjing Liu ◽

Ruiyao Hu ◽

Lulu Pei ◽

Yuming Xu ◽

Bo Song

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

T Cell ◽

Regulatory T Cell ◽

Cell Expansion ◽

Neuronal Apoptosis ◽

Infarct Volume ◽

Intraperitoneal Administration

Background: The interleukin (IL)-33 could promote proliferation of regulatory T lymphocytes (Tregs) which are negatively related with brain damage after ischemic stroke. How IL-33 works on Tregs after stroke is unclear. The purpose of this study was to investigate the role of IL-33 for Tregs-mediated neuroprotection and further expounded the mechanisms of protection in mice. Methods: In vitro study, primary mice neuronal cells were subjected to 3h oxygen-glucose deprivation (OGD). The vehicle or drug conditioned Tregs were applied to neurons at the time of induction of hypoxia respectively. Neuronal apoptosis, Tregs related cytokines were measured by MTT assay, Western blotting and enzyme-linked immune-sorbent assay (ELISA). In vivo study, Tregs were depleted by intraperitoneal administration of anti-CD25Ab. Intraperitoneal injection of IL-33 immediately post 60 min transient middle cerebral artery occlusion (tMCAO) modeling. The neurological function test at days 1, 3, 5, 7 and 14 after tMCAO. Infarct volume, Brain edema, cell death, percentage of Tregs and related cytokines were respectively measured by 2,3,5-triphenyltetrazolium chloride or MAP2 staining, dry-wet method, TUNEL staining, flow cytometry and immunofluorescence, Western blotting and ELISA. Results: The supernatant of IL-33-treated Tregs reduced neuronal apoptosis in the OGD model meanwhile elevated the production of Tregs related cytokines IL-10, IL-35 and TGF- β in vitro. Intraperitoneal administration of IL-33 significantly reduced infarct volume and stroke-induced cell death and improved sensorimotor functions. Notably, the protective effect of IL-33 was abolished in mice depleted of Tregs. IL-33 increased CD4+CD25+Foxp3+ Tregs in spleens, blood, and brain in vivo. Yet, ST2 blocking muted these IL-33 activities. Mechanistically, the protection of IL-33 was associated with reduced apoptosis protein and production of Tregs related cytokine. Conclusions: This study elucidated that IL-33 afforded neuroprotection against ischemic brain injury by enhancing ST2-dependent regulatory T-cell expansion and activation, which suggested a promising immune modulatory target for the treatment of stroke.

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Neuroprotective and Angiogenesis Effects of Levetiracetam Following Ischemic Stroke in Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.638209 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiang Yao ◽

Wenping Yang ◽

Zhendong Ren ◽

Haoran Zhang ◽

Dafa Shi ◽

...

Keyword(s):

Cerebral Cortex ◽

Ischemic Stroke ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Infarct Volume ◽

Hypoxia Inducible Factor ◽

Neuronal Cell ◽

Anti Inflammatory

Objective: The present study explored whether levetiracetam (LEV) could protect against experimental brain ischemia and enhance angiogenesis in rats, and investigated the potential mechanisms in vivo and in vitro.Methods: The middle cerebral artery was occluded for 60 min to induce middle cerebral artery occlusion (MCAO). The Morris water maze was used to measure cognitive ability. The rotation test was used to assess locomotor function. T2-weighted MRI was used to assess infarct volume. The neuronal cells in the cortex area were stained with cresyl purple. The anti-inflammatory effects of LEV on microglia were observed by immunohistochemistry. Enzyme-linked immunosorbent assays (ELISA) were used to measure the production of pro-inflammatory cytokines. Western blotting was used to detect the levels of heat shock protein 70 (HSP70), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1α (HIF-1α) in extracts from the ischemic cortex. Flow cytometry was used to observe the effect of LEV on neuronal cell apoptosis.Results: LEV treatment significantly increased the density of the surviving neurons in the cerebral cortex and reduced the infarct size (17.8 ± 3.3% vs. 12.9 ± 1.4%, p < 0.01) after MCAO. Concurrently, the time required to reach the platform for LEV-treated rats was shorter than that in the saline group on day 11 after MCAO (p < 0.01). LEV treatment prolonged the rotarod retention time on day 14 after MCAO (84.5 ± 6.7 s vs. 59.1 ± 6.2 s on day 14 compared with the saline-treated groups, p < 0.01). It also suppressed the activation of microglia and inhibited TNF-α and Il-1β in the ischemic brain (135.6 ± 5.2 pg/ml vs. 255.3 ± 12.5 pg/ml, 18.5 ± 1.3 pg/ml vs. 38.9 ± 2.3 pg/ml on day 14 compared with the saline-treated groups, p < 0.01). LEV treatment resulted in a significant increase in HIF-1α, VEGF, and HSP70 levels in extracts from the ischemic cerebral cortex. At the same time, LEV reduced neuronal cell cytotoxicity and apoptosis induced by an ischemic stroke (p < 0.01).Conclusion: LEV treatment promoted angiogenesis and functional recovery after cerebral ischemia in rats. These effects seem to be mediated through anti-inflammatory and antiapoptotic activities, as well as inducing the expression of HSP70, VEGF, and HIF-1α.

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Autophagy is Involved in Neuroprotective Effect of Alpha7 Nicotinic Acetylcholine Receptor on Ischemic Stroke

Frontiers in Pharmacology ◽

10.3389/fphar.2021.676589 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhe-Qi Xu ◽

Jing-Jing Zhang ◽

Ni Kong ◽

Guang-Yu Zhang ◽

Ping Ke ◽

...

Keyword(s):

Ischemic Stroke ◽

Signaling Pathway ◽

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Autophagy Flux ◽

Nicotinic Acetylcholine

The α7 nicotinic acetylcholine receptor (α7nAChR) belongs to the superfamily of cys loop cationic ligand-gated channels, which consists of homogeneous α7 subunits. Although our lab found that activation of α7nAChR could alleviate ischemic stroke, the mechanism is still unknown. Herein, we explored whether autophagy is involved in the neuroprotective effect mediated by α7nAChR in ischemic stroke. Transient middle cerebral artery occlusion (tMCAO) and oxygen and glucose deprivation (OGD/R) exposure were applied to in vivo and in vitro models of ischemic stroke, respectively. Neurological deficit score and infarct volume were used to evaluate outcomes of tMCAO in the in vivo study. Autophagy-related proteins were detected by Western blot, and autophagy flux was detected by using tandem fluorescent mRFP-GFP-LC3 lentivirus. At 24 h after tMCAO, α7nAChR knockout mice showed worse neurological function and larger infarct volume than wild-type mice. PNU282987, an α7nAChR agonist, protected against OGD/R-induced neuronal injury, enhanced autophagy, and promoted autophagy flux. However, the beneficial effects of PNU282987 were eliminated by 3-methyladenine (3-MA), an autophagy inhibitor. Moreover, we found that PNU282987 treatment could activate the AMPK-mTOR-p70S6K signaling pathway in the in vitro study, while the effect was attenuated by compound C, an AMPK inhibitor. Our results demonstrated that the beneficial effect on neuronal survival via activation of α7nAChR was associated with enhanced autophagy, and the AMPK-mTOR-p70S6K signaling pathway was involved in α7nAChR activation–mediated neuroprotection.

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Functional segregation of the human basal forebrain using resting state neuroimaging

10.1101/211086 ◽

2017 ◽

Author(s):

Ross D. Markello ◽

R. Nathan Spreng ◽

Wen-Ming Luh ◽

Adam K. Anderson ◽

Eve De Rosa

Keyword(s):

Functional Connectivity ◽

Resting State ◽

Basal Forebrain ◽

Nucleus Basalis ◽

Functional Networks ◽

List Type ◽

Functional Connections ◽

Diagonal Band ◽

Hippocampal Complex

AbstractThe basal forebrain (BF) is poised to play an important neuromodulatory role in brain re-gions important to cognition due to its broad projections and complex neurochemistry. While significant in vivo work has been done to elaborate BF function in nonhuman rodents and primates, comparatively limited work has examined the in vivo function of the human BF. In the current study we used multi-echo resting state functional magnetic resonance imaging (rs-fMRI) from 100 young adults (18-34 years) to assess the potential segregation of human BF nuclei as well as their associated projections. Bottom-up clustering of voxel-wise functional connectivity maps yielded adjacent functional clusters within the BF that closely aligned with the distinct, hypothesized nuclei important to cognition: the nucleus basalis of Meynert (NBM) and the me-dial septum/diagonal band of Broca (MS/DB). Examining their separate functional connections, the NBM and MS/DB revealed distinct projection patterns, suggesting a conservation of nuclei-specific functional connectivity with homologous regions known to be anatomically innervated by the BF. Specifically, the NBM demonstrated coupling with a widespread cortical network as well as the amygdala, whereas the MS/DB revealed coupling with a more circumscribed net-work, including the orbitofrontal cortex and hippocampal complex. Collectively, these in vivo rs-fMRI data demonstrate that the human BF nuclei support functional networks distinct as-pects of resting-state functional networks, suggesting the human BF may be a neuromodulatory hub important for orchestrating network dynamics.HighlightsThe basal forebrain NBM and the MS/DB support two distinct functional networksFunctional networks closely overlap with known anatomical basal forebrainBasal forebrain networks are distinct from known resting-state functional networks

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The Neuroprotective Effects of Insulin-Like Growth Factor 1 via the Hippo/YAP Signaling Pathway is Mediated by the PI3K/AKT Pathway Following Cerebral Ischemia-Reperfusion Injury

10.21203/rs.3.rs-187237/v1 ◽

2021 ◽

Author(s):

Pian Gong ◽

Yichun Zou ◽

Wei Zhang ◽

Qi Tian ◽

Shoumeng Han ◽

...

Keyword(s):

Ischemic Stroke ◽

Growth Factor ◽

Signaling Pathway ◽

Neuronal Death ◽

Infarct Volume ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Neuroprotective Effects

Abstract Insulin-like growth factor 1 (IGF-1) exhibits neuroprotective properties, such as vasodilatory and anti-inflammatory effects following ischemic stroke. However, the specific molecular mechanisms of action of IGF-1 following ischemic stroke remain elusive. We wanted to explore whether IGF-1 regulates Hippo/YAP signaling pathway, potentially via activation of the PI3K/AKT signaling pathway to exert its neuroprotective effects following ischemic stroke. In the in vitro study, we used oxygen–glucose deprivation to injure cultured PC12 and SH-5YSY cells, and cortical primary neurons. Cell viability was measured using CCK-8 assay. For the in vivo analyses, Sprague–Dawley rats were subjected to middle cerebral artery occlusion; neurological function was assessed using the neurological deficit score; infarct volume was measured using triphenyltetrazolium chloride staining, and neuronal death and apoptosis was evaluated by TUNEL staining, H&E staining and Nissl staining. Western blot was used to measure the levels of YAP/TAZ, PI3K and phosphorylated AKT (p-AKT) both in vitro and in vivo. We found that IGF-1 induced activation of YAP/TAZ, which resulted in improved cell viability in vitro, and decreased neurological deficits, neuronal death and apoptosis, and cerebral infarct volume in vivo. Notably, the neuroprotective effects of IGF-1 were reversed by an inhibitor of the PI3K/AKT signaling pathway, LY294002, which not only reduced expressions of PI3K and p-AKT, but also down-regulated expression of YAP/TAZ, leading to aggravation of neurological dysfunction. These findings indicate that neuroprotective effect of IGF-1 is partly realized by up-regulation of YAP/TAZ, which is mediated by activation of the PI3K/AKT signaling pathway following cerebral ischemic stroke.

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Abstract 44: Hdac3i Alleviated Ischemic Stroke Injury Through Modulating Aim2 Inflammasome and Microglia Polarization

Stroke ◽

10.1161/str.48.suppl_1.44 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Meijuan Zhang ◽

Mingxu Xia ◽

Qiuchen Zhao ◽

Yun Xu

Keyword(s):

Ischemic Stroke ◽

Infarct Volume ◽

Glucose Deprivation ◽

Vehicle Group ◽

Triphenyltetrazolium Chloride ◽

Bv2 Cells ◽

Severity Scores ◽

Microglia Polarization

Background: Inflammasome in microglia are critical to elicit inflammatory cascades in ischemic stroke. Histone deacetylases 3 (HDAC3) regulate acetylation states of histone and non-histone proteins and could be a powerful regulator of inflammatory process in stroke. Methods: Primary microglia, BV2 cells subjected to oxygen glucose deprivation (OGD) or LPS stimulation were applied to mimic inflammatory response in vitro . Middle cerebral artery occlusion (MCAO) model were applied to mimic acute stroke in vivo . Ischemic infarct volume and neurological functions were evaluated through 2,3,5-triphenyltetrazolium chloride (TTC) staining and Neurological Severity Scores (NSS) respectively. Expression of HDAC3, AIM2 inflammasome were detected by western blotting, PCR. Immunofluorescence was used to detect M1/M2 polarization. Luciferase activity of absent in melanoma 2 (AIM2) reporter promoter constructs was measured by fluorospectrophotometer. AIM2 knockdown and over-expression leti-virus were constructed to decrease or increase AIM2 expression. HDAC3 inhibitor RGFP966 was used to inhibit acetylation activity of HDAC3. Results: HDAC3 is widely distributed in cerebral cortex, lateral ventricular , hippocampus, cerebellar cortex ; HDAC3 and AIM2 expression were enhanced in LPS stimulated-microglia and MCAO model. A marked stimulatory effect of RGFP966 on H3K9Ac was observed in nuclear extracts form BV2 cells at the dosage of 15 uM. Treatment of RGFP966 increased both IL-4-stimulated expression of Ym-1 and CD206 at 4 h, 10 h, 24 h, 48 h. AIM2, NLRP-1 and NLRP3 significantly increased in MCAO+Vehicle group compared to sham group, but decreased in MCAO+RGFP966 group. RGFP966 inhibited the elevation of circulatory IL-18 and IL-1β induced by stroke. RGFP966 decreased infracted size and alleviated neurological deficit. Conclusions: HDAC3i alleviated ischemic stroke injury through modulating AIM2 inflammasome and microglia polarization. Selective HDAC3 inhibitor-RGFP966 could be a potential medication for combating ischemic brain injury.

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Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem®-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke

International Journal of Molecular Sciences ◽

10.3390/ijms19123782 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3782 ◽

Cited By ~ 10

Author(s):

Kristine Ravina ◽

Denise Briggs ◽

Sezen Kislal ◽

Zuha Warraich ◽

Tiffany Nguyen ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Recovery ◽

Neurotrophic Factor ◽

Infarct Volume ◽

Brain Derived Neurotrophic Factor ◽

Artery Occlusion ◽

Sensorimotor Function ◽

Neural Repair ◽

Adhesive Removal ◽

Cerebral Artery Occlusion

Ischemic stroke is a leading cause of death and disability worldwide. Potential therapeutics aimed at neural repair and functional recovery are limited in their blood-brain barrier permeability and may exert systemic or off-target effects. We examined the effects of brain-derived neurotrophic factor (BDNF), delivered via an extended release HyStem®-C hydrogel implant or vehicle, on sensorimotor function, infarct volume, and neuroinflammation, following permanent distal middle cerebral artery occlusion (dMCAo) in rats. Eight days following dMCAo or sham surgery, treatments were implanted directly into the infarction site. Rats received either vehicle, BDNF-only (0.167 µg/µL), hydrogel-only, hydrogel impregnated with 0.057 µg/µL of BDNF (hydrogel + BDNFLOW), or hydrogel impregnated with 0.167 µg/µL of BDNF (hydrogel + BDNFHIGH). The adhesive removal test (ART) and 28-point Neuroscore (28-PN) were used to evaluate sensorimotor function up to two months post-ischemia. The hydrogel + BDNFHIGH group showed significant improvements on the ART six to eight weeks following treatment and their behavioral performance was consistently greater on the 28-PN. Infarct volume was reduced in rats treated with hydrogel + BDNFHIGH as were levels of microglial, phagocyte, and astrocyte marker immunoexpression in the corpus striatum. These data suggest that targeted intracerebral delivery of BDNF using hydrogels may mitigate ischemic brain injury and restore functional deficits by reducing neuroinflammation.

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HMGB1-triggered inflammation inhibition of notoginseng leaf triterpenes against cerebral ischemia and reperfusion injury via MAPK and NF-κB signaling pathways

Biomolecules ◽

10.3390/biom9100512 ◽

2019 ◽

Vol 9 (10) ◽

pp. 512 ◽

Cited By ~ 14

Author(s):

Xie ◽

Zhu ◽

Dong ◽

Nan ◽

Meng ◽

...

Keyword(s):

Ischemic Stroke ◽

Cerebral Ischemia ◽

Infarct Volume ◽

Neuronal Loss ◽

Ischemia And Reperfusion ◽

Protective Effects ◽

Ischemia And Reperfusion Injury ◽

Neuroprotective Effects ◽

Cerebral Ischemia And Reperfusion

Ischemic stroke is a clinically common cerebrovascular disease whose main risks include necrosis, apoptosis and cerebral infarction, all caused by cerebral ischemia and reperfusion (I/R) injury. This process has particular significance for the treatment of stroke patients. Notoginseng leaf triterpenes (PNGL), as a valuable medicine, have been discovered to have neuroprotective effects. However, it was not confirmed that whether PNGL may possess neuroprotective effects against cerebral I/R injury. To explore the neuroprotective effects of PNGL and their underlying mechanisms, a middle cerebral artery occlusion/reperfusion (MCAO/R) model was established. In vivo results suggested that in MCAO/R model rats, PNGL pretreatment (73.0, 146, 292 mg/kg) remarkably decreased infarct volume, reduced brain water content, and improved neurological functions; moreover, PNGL (73.0, 146, 292 mg/kg) significantly alleviated blood-brain barrier (BBB) disruption and inhibited neuronal apoptosis and neuronal loss caused by cerebral I/R injury, while PNGL with a different concertation (146, 292 mg/kg) significantly reduced the concentrations of IL-6, TNF-α, IL-1 β, and HMGB1 in serums in a dose-dependent way, which indicated that inflammation inhibition could be involved in the neuroprotective effects of PNGL. The immunofluorescence and western blot analysis showed PNGL decreased HMGB1 expression, suppressed the HMGB1-triggered inflammation, and inhibited microglia activation (IBA1) in hippocampus and cortex, thus dose-dependently downregulating inflammatory cytokines including VCAM-1, MMP-9, MMP-2, and ICAM-1 concentrations in ischemic brains. Interestingly, PNGL administration (146 mg/kg) significantly downregulated the levels of p-P44/42, p-JNK1/2 and p-P38 MAPK, and also inhibited expressions of the total NF-κB and phosphorylated NF-κB in ischemic brains, which was the downstream pathway triggered by HMGB1. All of these results indicated that the protective effects of PNGL against cerebral I/R injury could be associated with inhibiting HMGB1-triggered inflammation, suppressing the activation of MAPKs and NF-κB, and thus improved cerebral I/R-induced neuropathological changes. This study may offer insight into discovering new active compounds for the treatment of ischemic stroke.

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Neuroprotective Effects of Guanosine in Ischemic Stroke—Small Steps towards Effective Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22136898 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6898

Author(s):

Karol Chojnowski ◽

Mikolaj Opielka ◽

Wojciech Nazar ◽

Przemyslaw Kowianski ◽

Ryszard T. Smolenski

Keyword(s):

Ischemic Stroke ◽

Brain Ischemia ◽

Excitatory Amino Acid ◽

Infarct Volume ◽

In Vivo Studies ◽

Amino Acid Transporters ◽

Tissue Slices ◽

Neuroprotective Effects

Guanosine (Guo) is a nucleotide metabolite that acts as a potent neuromodulator with neurotrophic and regenerative properties in neurological disorders. Under brain ischemia or trauma, Guo is released to the extracellular milieu and its concentration substantially raises. In vitro studies on brain tissue slices or cell lines subjected to ischemic conditions demonstrated that Guo counteracts destructive events that occur during ischemic conditions, e.g., glutaminergic excitotoxicity, reactive oxygen and nitrogen species production. Moreover, Guo mitigates neuroinflammation and regulates post-translational processing. Guo asserts its neuroprotective effects via interplay with adenosine receptors, potassium channels, and excitatory amino acid transporters. Subsequently, guanosine activates several prosurvival molecular pathways including PI3K/Akt (PI3K) and MEK/ERK. Due to systemic degradation, the half-life of exogenous Guo is relatively low, thus creating difficulty regarding adequate exogenous Guo distribution. Nevertheless, in vivo studies performed on ischemic stroke rodent models provide promising results presenting a sustained decrease in infarct volume, improved neurological outcome, decrease in proinflammatory events, and stimulation of neuroregeneration through the release of neurotrophic factors. In this comprehensive review, we discuss molecular signaling related to Guo protection against brain ischemia. We present recent advances, limitations, and prospects in exogenous guanosine therapy in the context of ischemic stroke.

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