scholarly journals Lumbrokinase regulates endoplasmic reticulum stress through IRE1 signaling to improve neurological deficits in ischemic stroke

2021 ◽  
Author(s):  
Yi-Hsin Wang ◽  
Jiuan-Miaw Liao ◽  
Ke-Min Chen ◽  
Hsing-Hui Su ◽  
Pei-Hsun Liu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Ischemic Stroke ◽  
Functional Disability ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neurological Dysfunction ◽  
Neurological Deficits ◽  
Receptor Protein ◽  
Stroke Treatment ◽  
Post Stroke

Abstract Background Ischemic stroke is characterized by the loss of cerebral blood flow, which frequently leads to neurological deficits. Therefore, minimizing post-stroke functional disability is an important research topic. The fibrinogen-depleting agent lumbrokinase has been used to improve myocardial perfusion in symptomatic stable angina and to prevent secondary ischemic stroke. In this study, we aimed to clarify the neuroprotection of lumbrokinase on ischemic stroke and whether improve neurological dysfunction. We explored the neuroprotection and the underlying mechanisms of lumbrokinase in C57BL/6 mice subjected to permanent middle cerebral artery occlusion. Results Lumbrokinase at 1 mg/kg significantly attenuated the infarct volume and improved the neurological dysfunction. Lumbrokinase dramatically decreased the expressions of the endoplasmic reticulum (ER) transmembrane receptor protein inositol-requiring enzyme-1 (IRE1) and its downstream transcription factor, X-box binding protein-1, caspase-12, and nuclear factor kappa B activity. Moreover, lumbrokinase significantly inhibited apoptosis and autophagy and decreased the expression levels of the NOD-like receptor 3 inflammasome, caspase-1, and interleukin-1β compared with the vehicle treatment. Conclusions We suggest that post-stroke treatment with lumbrokinase protects against ischemic stroke by regulating ER stress through the IRE1 signaling pathways to inhibit apoptosis, autophagy, and inflammatory responses.

scholarly journals Thiamet G mediates neuroprotection in experimental stroke by modulating microglia/macrophage polarization and inhibiting NF-κB p65 signaling

2016 ◽  
Vol 37 (8) ◽  
pp. 2938-2951 ◽  
Author(s):  
Yating He ◽  
Xiaofeng Ma ◽  
Daojing Li ◽  
Junwei Hao
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Bv2 Cells ◽  
Anti Inflammatory

Inflammatory responses are accountable for secondary injury induced by acute ischemic stroke (AIS). Previous studies indicated that O-GlcNAc modification (O-GlcNAcylation) is involved in the pathology of AIS, and increase of O-GlcNAcylation by glucosamine attenuated the brain damage after ischemia/reperfusion. Inhibition of β-N-acetylglucosaminidase (OGA) with thiamet G (TMG) is an alternative option for accumulating O-GlcNAcylated proteins. In this study, we investigate the neuroprotective effect of TMG in a mouse model of experimental stroke. Our results indicate that TMG administration either before or after middle cerebral artery occlusion (MCAO) surgery dramatically reduced infarct volume compared with that in untreated controls. TMG treatment ameliorated the neurological deficits and improved clinical outcomes in neurobehavioral tests by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Additionally, TMG administration reduced the number of Iba1+ cells in MCAO mice, decreased expression of the M1 markers, and increased expression of the M2 markers in vivo. In vitro, M1 polarization of BV2 cells was inhibited by TMG treatment. Moreover, TMG decreased the expression of iNOS and COX2 mainly by suppressing NF-κB p65 signaling. These results suggest that TMG exerts a neuroprotective effect and could be useful as an anti-inflammatory agent for ischemic stroke therapy.

scholarly journals Ambroxol Upregulates Glucocerebrosidase Expression to Promote Neural Stem Cells Differentiation Into Neurons Through Wnt/β-Catenin Pathway After Ischemic Stroke

2021 ◽  
Vol 13 ◽  
Author(s):  
Hongfei Ge ◽  
Chao Zhang ◽  
Yang Yang ◽  
Weixiang Chen ◽  
Jun Zhong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Infarct Volume ◽  
Basic Knowledge ◽  
Brain Disorders ◽  
Potential Mechanism ◽  
Stroke Patients ◽  
Stroke Treatment ◽  
Post Stroke

Ischemic stroke has been becoming one of the leading causes resulting in mortality and adult long-term disability worldwide. Post-stroke pneumonia is a common complication in patients with ischemic stroke and always associated with 1-year mortality. Though ambroxol therapy often serves as a supplementary treatment for post-stroke pneumonia in ischemic stroke patients, its effect on functional recovery and potential mechanism after ischemic stroke remain elusive. In the present study, the results indicated that administration of 70 mg/kg and 100 mg/kg enhanced functional recovery by virtue of decreasing infarct volume. The potential mechanism, to some extent, was due to promoting NSCs differentiation into neurons and interfering NSCs differentiation into astrocytes through increasing GCase expression to activate Wnt/β-catenin signaling pathway in penumbra after ischemic stroke, which advanced basic knowledge of ambroxol in regulating NSCs differentiation and provided a feasible therapy for ischemic stroke treatment, even in other brain disorders in clinic.

Abstract W P199: Deficiency of Glia Maturation Factor Abrogates Brain Injury and Inflammation in a Murine Model of Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Mohammad M Khan ◽  
Asgar Zaheer
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Proinflammatory Cytokines ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Glia Maturation Factor ◽  
Western Blots ◽  
Ischemic Brain ◽  
Maturation Factor

Background and purpose: Glia maturation factor (GMF), a brain specific protein, discovered and characterized in our laboratory, induces expression of proinflammatory cytokines/ chemokines in the central nervous system (CNS). Recently, it has been demonstrated that deficiency of GMF mitigates neuronal damage in tissue culture cell and animal models of neurodegeneration. Since, GMF expression in brain enhances inflammation; we tested the hypothesis that deficiency of GMF abrogates the inflammatory responses in experimental model of ischemic stroke. Methods: Transient focal cerebral ischemia was induced by 1 hour of occlusion of the right middle cerebral artery (MCAO) with a 7.0 monofilament in GMF-containing wild type (Wt) and GMF-deficient (GMF-KO) mice. Mice were anesthetized with 1-1.5% isoflurane mixed with medical oxygen. Body temperature was maintained at 37°C ± 1.0 using a heating pad. At 23 hours after ischemia/reperfusion, mice were tested for neurological scores and were sacrificed for the infarct volume and estimation of inflammatory responses. Immunohistochemistry and western blots were used to analyze the expression and activation of glial cells, and levels of NF-κB in ischemic brain hemisphere. Results: We found that levels of GMF significantly increased in MCAO mice compared to saline treated control mice. Next we found that GMF-KO mice exhibited significantly decreased infarct volume, and reduced neurological deficits compared to Wt mice. The decrease in infarct volume and neurological deficits in GMF-KO mice were correlated with a less activation of glia cells, downregulation of NF-κB and suppression of proinflammatory cytokines/chemokine in the ischemic region. Conclusions: In conclusion, present study provides the first evidence that deficiency of GMF reduces brain injury and inflammation after ischemic stroke and suggests that the effective suppression of endogenous GMF-function will prove to be an effective and selective strategy to slow deleterious inflammatory processes in ischemic brain injury. Keywords: Glia maturation factor; Ischemic stroke; Inflammation; Nuclear factor-κB; Cytokines

scholarly journals Loss of Gucy1a3 Causes Poor Post-Stroke Recovery by Reducing Angiogenesis Via the HIF-1α/VEGFA Signaling Pathway in Mice

2022 ◽  
Author(s):  
Man Luo ◽  
Dongcan Mo ◽  
LiuYu Liu ◽  
Jianli Li ◽  
Jing Lin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Infarct Volume ◽  
Hypoxia Inducible Factor ◽  
Soluble Guanylyl Cyclase ◽  
Stroke Recovery ◽  
Neurological Deficits ◽  
Wild Type ◽  
Expression Levels ◽  
Post Stroke

Abstract Ischemic stroke is a common and debilitating disease that can cause permanent neurological damage. Gucy1a3, which encodes the α1 subunit of soluble guanylyl cyclase, has been reported to be associated with functional recovery after ischemic stroke. However, the mechanism is still not well understood. In the present study, we investigated the effects of Gucy1a3 on (i) post-stroke recovery; (ii) vascular endothelial growth factor A (VEGFA) and hypoxia inducible factor 1 alpha (HIF-1α) expression; and (iii) angiogenesis after ischemic stroke. A permanent middle cerebral artery occlusion (pMCAO) model was established using wild-type and Gucy1a3 knockout C57BL/6J male mice. Neurological deficits, infarct volume, microvascular density, and VEGFA and HIF-1α expression levels of mice were evaluated. Our results suggest that loss of Gucy1a3 increased the infarct volume and aggravated neurological deficits after pMCAO. In addition, the Gucy1a3 knockout brains exhibited significantly lower microvessel densities and VEGFA and HIF-1α expression levels than the wild-type brains at 96 hours post-pMCAO. The study shows that the expression of GUCY1A3 after ischemic stroke may play a substantial role in neurological function recovery and is related to angiogenesis in the peri-infarct region. The beneficial effects of GUCY1A3 might be mediated through the HIF-1α/VEGFA signaling pathway.

scholarly journals Cerebral endothelial cell-derived small extracellular vesicles enhance neurovascular function and neurological recovery in rat acute ischemic stroke models of mechanical thrombectomy and embolic stroke treatment with tPA

2021 ◽  
pp. 0271678X2199298
Author(s):  
Chao Li ◽  
Chunyang Wang ◽  
Yi Zhang ◽  
Owais K Alsrouji ◽  
Alex B Chebl ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Mechanical Thrombectomy ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Therapeutic Effects ◽  
Vessel Occlusion ◽  
Healthy Human ◽  
Stroke Treatment

Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) leads to incomplete reperfusion. Using rat models of embolic and transient middle cerebral artery occlusion (eMCAO and tMCAO), we investigated the effect on stroke outcomes of small extracellular vesicles (sEVs) derived from rat cerebral endothelial cells (CEC-sEVs) in combination with tPA (CEC-sEVs/tPA) as a treatment of eMCAO and tMCAO in rat. The effect of sEVs derived from clots acquired from patients who had undergone mechanical thrombectomy on healthy human CEC permeability was also evaluated. CEC-sEVs/tPA administered 4 h after eMCAO reduced infarct volume by ∼36%, increased recanalization of the occluded MCA, enhanced cerebral blood flow (CBF), and reduced blood-brain barrier (BBB) leakage. Treatment with CEC-sEVs given upon reperfusion after 2 h tMCAO significantly reduced infarct volume by ∼43%, and neurological outcomes were improved in both CEC-sEVs treated models. CEC-sEVs/tPA reduced a network of microRNAs (miRs) and proteins that mediate thrombosis, coagulation, and inflammation. Patient-clot derived sEVs increased CEC permeability, which was reduced by CEC-sEVs. CEC-sEV mediated suppression of a network of pro-thrombotic, -coagulant, and -inflammatory miRs and proteins likely contribute to therapeutic effects. Thus, CEC-sEVs have a therapeutic effect on acute ischemic stroke by reducing neurovascular damage.

Abstract TP224: Interleukin-37 Level is Elevated in Acute Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Saif Bushnaq ◽  
Atif Zafar ◽  
Kempuraj Duraisamy ◽  
Nudrat Tasneem ◽  
Mohammad M Khan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Inflammatory Responses ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Delayed Presentation ◽  
Stroke Patients ◽  
Post Stroke ◽  
Urine And Serum ◽  
Serum And Urine

Background: Interleukin-37 (IL-37) is a new member of IL-1 cytokine family with a defined role as a negative feedback inhibitor of pro-inflammatory responses. IL-37 has yet to be evaluated in non-immune neurological diseases like ischemic or hemorrhagic stroke. This study aimed to measure the urine and serum IL-37 levels in patients with acute ischemic stroke. Method: Twelve patients consented for the study. Two sets of serum and urine samples were obtained and analyzed; one upon admission to the hospital, and the second the next morning after overnight fasting. The trends in serum level of IL-37 in 5 stroke patients, while trends in urine level of 6 patients were available, measured by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Prior studies with healthy volunteers as control group have consistently showed IL-37 plasma level around or less than 65 pg/ml with maximum normal levels on ELISA approximated at 130 pg/ml. Results: IL-37 level in urine in stroke patients ranged from 297 - 4467. IL-37 levels were in the range of 300s to 1000s in patients with ischemic stroke compared with reported healthy controls in literature where the level was always less than 90. Three of these 10 patients presented within 3 hours of stroke onset with IL-37 serum levels being 2655 pg/ml, 3517 pg/ml and 5235 pg/ml. In all others, it ranged much less than that, with the trend of delayed presentation giving less IL-37 levels, both in urine and serum. There were no clear differences found in patients with or without tPA, diabetes, hyperlipidemia and high blood pressure in our small study. Conclusion: The study shows a rather stable elevation of IL-37 levels post-ischemic stroke, which if compared to available data from other studies, is 3-10 times elevated after acute ischemic stroke with an uptrend in the first few days. IL-37 plays some role in mediating post-stroke inflammation with significant rise in serum and urine IL-37 levels suggesting a key role of this novel cytokine in post-stroke pathology. This is the first ever reported study measuring and trending IL-37 levels in human plasma after an acute ischemic stroke.

Abstract T P228: Ischemic Stroke Results in Increased Activity of the Neuroprotective Angiotensin Converting Enzyme 2 in Rat Brain and Serum

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Douglas M Bennion ◽  
Emily Haltigan ◽  
Alexander J Irwin ◽  
Daniel L Purich ◽  
Colin Sumners
Keyword(s):  
Cerebral Cortex ◽  
Ischemic Stroke ◽  
Angiotensin Converting Enzyme ◽  
Rat Cerebral Cortex ◽  
Mrna Levels ◽  
Converting Enzyme ◽  
Stroke Treatment ◽  
Angiotensin Converting Enzyme 2 ◽  
Post Stroke ◽  
Rebound Increase

Background: Recent studies show that pharmacological induction of the angiotensin converting enzyme 2/angiotensin-(1-7)/mas [ACE2-Ang-(1-7)-Mas] axis, a protective pathway of the renin angiotensin system, elicits neuroprotection in ischemic stroke. However, endogenous levels and activity of the components of this axis in the brain and serum following stroke are not well established. Here, we assessed the post-stroke activity and expression of ACE2 in rat cerebral cortex and serum after ischemic stroke in rats, in the absence or presence of an ACE2 activator. Methods: Sprague Dawley rats underwent sham surgery or endothelin-1-induced middle cerebral artery occlusion (ET-1 MCAO). Activity of ACE2 was analyzed within serum and cerebral cortical tissue samples using a fluorometric assay, and mRNA levels were assessed by qRT-PCR. In an additional experiment, rats received daily intraperitoneal administration of diminazene aceturate (DIZE), a putative ACE2 activator, or vehicle after ET-1 MCAO. Data are normalized to corresponding control values and expressed as means ± SEM with a significance of p<0.05. Results: ACE2 activity levels were significantly increased in ischemic brain cortex at 4, 12, and 24 h after a stroke (4h: 237.1±46.1%; 12h: 212.4±12.8%; 24h: 191.6±19.1%) versus rats with sham strokes. Paradoxically, there was a significant decrease in ACE2 mRNA levels in the ischemic cortex at 24h (0.71±0.1) compared to shams (1.0±0.08). After decreasing in activity at 4h after stroke, serum ACE2 activity was increased at 24h in stroked rats (96.08±9.4%) versus shams (70.80±7.1%). Post-stroke treatment with DIZE (7.5 mg/kg) resulted in significantly increased ACE2 activity in serum (213.7±49.8%) versus controls, two days following stroke. Conclusions: Activity of the protective enzyme ACE2 is increased in rat cerebral cortex following stroke, with a rebound increase in serum activity. Post-stroke treatment with an ACE2 activator resulted in significantly increased ACE2 activity in serum. These results suggest that stroke therapeutics designed to target the ACE2/Ang-(1-7)/Mas axis may act in synergy with endogenous changes in the acute post-stroke setting, lending promise to their further study as potential neuroprotective agents.

Abstract TP111: Activation of the Brain Renin-Angiotensin System by Translational Approaches Following Stroke Onset Is Neuroprotective in a Rat Model of Ischemic Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Douglas M Bennion ◽  
Lauren Donnangelo ◽  
David Pioquinto ◽  
Robert Regenhardt ◽  
Mohan K Raizada ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Volume ◽  
Renin Angiotensin System ◽  
Cerebral Infarct ◽  
Intraventricular Administration ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Post Stroke ◽  
Neurologic Deficits ◽  
The Brain

Background: Toward discovering novel stroke therapies, recent research has shown that activation of the newly-discovered angiotensin converting enzyme 2/angiotensin-(1-7)/mas (ACE2/Ang-(1-7)/Mas) pathway, a counter-regulatory axis of the brain renin-angiotensin system, is neuroprotective in ischemic stroke in rats. Specifically, intraventricular administration of the novel ACE2 activator diminazine aceturate (DIZE) before and during an ischemic stroke decreases cerebral infarct and neurologic deficits. Efficacy must now be demonstrated using minimally-invasive methods if this therapy is to be translated to the care of human patients. In this study, we assessed the hypothesis that systemic administration of DIZE post ischemic stroke would be neuroprotective. Methods: Adult male Sprague-Dawley rats underwent ischemic stroke by endothelin-1 induced middle cerebral artery occlusion and were randomly divided into 2 groups (n=9-10/set): 1) intraperitoneal (IP) administrations of DIZE (7.5 mg/kg) at 4, 24, and 48 h after stroke; 2) IP administrations of 0.9% saline vehicle at the same time points. At 24 and 72 h after stroke, rats underwent blinded neurologic assessments. Immediately following the 72 h tests, animals were sacrificed, cerebral infarct volumes assessed by TTC staining, and IL-1β expression in the stroke region analyzed by rt-PCR. Data are expressed as mean ± SEM with significance inferred at p<0.05. Results: Mean infarct volume was significantly decreased by IP injections of DIZE (9.4% ± 4.35) as compared to control (22.8%±3.6, p=0.039). At 24 h post stroke, neurologic deficits (Garcia Scale) were significantly improved in the DIZE treated group (16.7±0.40) versus the saline group (15.22±0.57, p=0.037). Although DIZE tended to improve neurologic deficits 72 h post stroke, this trend was not significant. Finally, DIZE treatment significantly reduced mRNA expression of IL-1β (0.43 ± 0.14) in the cerebral cortical stroke region as compared to saline treatment (1.47±0.08, p=0.001). Conclusions: Our findings suggest that targeting the ACE2/Ang-(1-7)/Mas axis post stroke can improve function, decrease inflammation, and reduce infarct volume - a significant translational step in brain renin-angiotensin system research.

NLRP3 inflammasome in ischemic stroke: As possible therapeutic target

2019 ◽  
Vol 14 (6) ◽  
pp. 574-591 ◽  
Author(s):  
Masoumeh Alishahi ◽  
Maryam Farzaneh ◽  
Farhoodeh Ghaedrahmati ◽  
Armin Nejabatdoust ◽  
Alireza Sarkaki ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Receptor Protein ◽  
Current Evidence ◽  
Related Factor ◽  
Type I ◽  
Micro Rnas ◽  
Extracellular Environment ◽  
Inflammasome Inhibitors

Inflammation is a devastating pathophysiological process during stroke, a devastating disease that is the second most common cause of death worldwide. Activation of the NOD-like receptor protein (NLRP3)-infammasome has been proposed to mediate inflammatory responses during ischemic stroke. Briefly, NLRP3 inflammasome activates caspase-1, which cleaves both pro-IL-1 and pro-IL-18 into their active pro-inflammatory cytokines that are released into the extracellular environment. Several NLRP3 inflammasome inhibitors have been promoted, including small molecules, type I interferon, micro RNAs, nitric oxide, and nuclear factor erythroid-2 related factor 2 (Nrf2), some of which are potentially efficacious clinically. This review will describe the structure and cellular signaling pathways of the NLRP3 inflammasome during ischemic stroke, and current evidence for NLRP3 inflammasome inhibitors.

scholarly journals The Role of Alpha-Lipoic Acid in the Pathomechanism of Acute Ischemic Stroke

2018 ◽  
Vol 48 (1) ◽  
pp. 42-53 ◽  
Author(s):  
Qingqing Wang ◽  
Chengmei Lv ◽  
Yongxin Sun ◽  
Xu Han ◽  
Shan Wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Lipoic Acid ◽  
Nuclear Translocation ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Phenotype

Background/Aims: Ischemic stroke results in increased cerebral infarction, neurological deficits and neuroinflammation. The underlying mechanisms involving the anti-inflammatory and neuroprotective properties of α-Lipoic acid (α-LA) remain poorly understood. Herein, we investigated the potential role of α-LA in a middle cerebral artery occlusion (MCAO) rat model and an in vitro lipopolysaccharide (LPS)-induced microglia inflammation model. Methods: In the in vivo study, infarct volume was examined by TTC staining and Garcia score was used to evaluate neurologic recovery. The cytokines were evaluated by enzyme-linked immunosorbent assay, and protein expression of microglia phenotype and NF-κB were measured using western blot. In the in vitro study, the expressions of microglia M1/M2 phenotype were evaluated using qRT-PCR, and immunofluorescence staining was used to assess the nuclear translocation of NF-κB. Results: Both 20 mg/kg and 40 mg/kg of α-LA alleviated infarct size, brain edema, and neurological deficits. Furthermore, α-LA induced the polarization of microglia to the M2 phenotype, modulated the expression of IL-1β, IL-6, TNF-α and IL-10, and attenuated the activation of NF-κB after MCAO. α-LA inhibited the expression of M1 markers, increased activation of the M2 markers, and suppressed the nuclear translocation of NF-κB in LPS-stimulated BV2 microglia. Conclusions: α-LA improved neurological outcome in experimental stroke via modulating microglia M1/M2 polarization. The potential mechanism of α-LA might be mediated by inhibition of NF-κB activation via regulating phosphorylation and nuclear translocation of p65.

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