scholarly journals Effect of Tetramethylpyrazine on Neuroplasticity after Transient Focal Cerebral Ischemia Reperfusion in Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Junbin Lin ◽  
Chizi Hao ◽  
Yu Gong ◽  
Ying Zhang ◽  
Ying Li ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Synaptic Cleft ◽  
Artery Occlusion ◽  
Neurological Function ◽  
Group Model ◽  
Model Group ◽  
Transient Focal Cerebral Ischemia ◽  
Transmission Electron

Tetramethylpyrazine (TMP) has been widely used in ischemic stroke in China. The regulation of neuroplasticity may underlie the recovery of some neurological functions in ischemic stroke. Middle cerebral artery occlusion (MCAO) model was established in this study. Rats were divided into three groups: sham group, model group, and TMP group. The neurological function was evaluated using modified neurological severity score (mNSS). Following the neurological function test, expression of synaptophysin (SYP) and growth-associated protein 43 (GAP-43) were analyzed through immunohistochemistry at 3 d, 7 d, 14 d, and 28 d after MCAO. Finally, the synaptic structural plasticity was investigated using transmission electron microscopy (TEM). The TMP group showed better neurological function comparing to the model group. SYP levels increased gradually in ischemic penumbra (IP) in the model group and could be enhanced by TMP treatment at 7 d, 14 d, and 28 d, whereas GAP-43 levels increased from 3 d to 7 d and thereafter decreased gradually from 14 d to 28 d in the model group, which showed no significant improvement in the TMP group. The results of TEM showed a flatter synaptic interface, a thinner postsynaptic density (PSD), and a wider synaptic cleft in the model group, and the first two alterations could be ameliorated by TMP. Then, a Pearson’s correlation test revealed mNSS markedly correlated with SYP and synaptic ultrastructures. Taken together, TMP is capable of promoting functional outcome after ischemic stroke, and the mechanisms may be partially associated with regulation of neuroplasticity.

Protective Effect of Capparis spinosa Extract Against Focal Cerebral Ischemia-Reperfusion Injury in Rats

2021 ◽  
Vol 21 ◽  
Author(s):  
Hassan Rakhshandeh ◽  
Samira Asgharzade ◽  
Mohammad Bagher Khorrami ◽  
Fatemeh Forouzanfar
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Ischemia Reperfusion Injury ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Public Health Problem ◽  
Artery Occlusion ◽  
Stroke Group ◽  
Capparis Spinosa

Background: Ischemic stroke is a serious public health problem. Despite extensive research focusing on the area, little is known about novel treatments. Objective: In this study, we aimed to investigate the effects of Capparis spinosa (C. spinosa) extract in the middle cerebral artery occlusion (MCAO) model of ischemic stroke. Methods: Wistar rats underwent 30-min MCAO-induced brain ischemia followed by 24 h of reperfusion. C. spinose was administrated orally once a day for 7 days before the induction of MCAO. The neurologic outcome, infarct volume (TTC staining), histological examination, and markers of oxidative stress, including total thiol content and malondialdehyde (MDA) levels, were measured 24 hr. after the termination of MCAO. Results: Pretreatment with C. spinosa, reduced neurological deficit score, histopathological alterations, and infarct volume in treated groups compared to stroke group. Furthermore, pretreatment with C. spinosa extract significantly reduced the level of MDA with concomitant increases in the levels of thiol in the brain tissues compared with the stroke group. Conclusion: Our study demonstrates that C. spinosa extract effectively protects MCAO injury through attenuation of suppressing oxidative stress.

scholarly journals Targeting Platelet GPVI Plus rt-PA Administration but Not α2β1-Mediated Collagen Binding Protects against Ischemic Brain Damage in Mice

2019 ◽  
Vol 20 (8) ◽  
pp. 2019 ◽  
Author(s):  
Michael K. Schuhmann ◽  
Peter Kraft ◽  
Michael Bieber ◽  
Alexander M. Kollikowski ◽  
Harald Schulze ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Recombinant Tissue Plasminogen Activator ◽  
Artery Occlusion ◽  
Stroke Outcome ◽  
Platelet Surface ◽  
Glycoprotein Vi ◽  
Stroke Study ◽  
Increased Risk

Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2−/− mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.

Abstract P487: Cerebral Endothelial Cell-Derived Small Extracellular Vesicles Enhance Neurovascular Function and Neurological Recovery in Rat Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Chao Li ◽  
Chunyang Wang ◽  
Yi Zhang ◽  
Owais K Alsrouji ◽  
Alex B Chebl ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Therapeutic Effect ◽  
Extracellular Vesicles ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Vessel Occlusion ◽  
Western Blots ◽  
Neurological Outcomes ◽  
Transmission Electron

Background: Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) often leads to incomplete reperfusion. There is a compelling need to develop therapies to enhance the perfusion and to improve neurological outcomes. Methods: Using rat models of embolic middle cerebral artery occlusion (eMCAO) and transient MCAO (tMCAO), we investigated the effect of small extracellular vesicles (sEVs) derived from healthy rat cerebral endothelial cells (CECs) administered intravenously in combination with tPA (CECs/tPA) and as an acute intraarterial adjunct therapy with mechanical reperfusion on stroke outcomes. Recanalization, cerebral blood flow (CBF), and blood-brain barrier (BBB) permeability were analyzed. MicroRNAs (miRs) and proteins were analyzed in CECs harvested from ischemic rats by RT-PCR and Western blots. Transmission electron microscopy was employed to analyze the brain distribution of CEC-sEVs. The effect of sEVs derived from clots acquired from patients undergone thrombectomy was tested on human CEC permeability. Results: CEC-sEVs/tPA given 4h after eMCAO or CEC-sEVs given upon reperfusion after 2h tMCAO significantly reduced infarct volume by ~36% and ~43%, respectively, and robustly improved neurological outcomes compared with tPA or ischemia/reperfusion alone (n=10 rats/group). CEC-sEVs/tPA and upon reperfusion after eMCAO or tMCAO, resepectively, significantly increased recanalization of the occluded MCA, enhanced CBF and reduced BBB leakage. CEC-sEVs/tPA substantially reduced a network of microRNAs and proteins that mediate thrombosis, coagulation and inflammation in CECs. Moreover, CEC-sEVs intravenously administered crossed the BBB and were internalized by CECs cells, astrocytes, and neurons. Stroke patient-clot derived exosomes impaired human CEC permeability and upregulated pro-inflammatory and -coagulatant proteins, which were blocked by CEC-sEVs. Conclusion: CEC-sEVs have a therapeutic effect on acute ischemic stroke in rats by reducing neurovascular damage. Suppressing the network of pro-thrombotic, -coagulant and -inflammatory microRNAs and proteins in CECs by CEC-sEVs likely contributes to the therapeutic effect of CEC-sEVs.

Abstract T P247: Neuronal Sirt1 Activation Negatively Regulates Rho Kinase in Photothrombotic Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Yong-Joo Ahn ◽  
Maya Hwewon Kim ◽  
Eun-Hye Lee ◽  
Ye-Rim Kwon ◽  
Wenliang Zhong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Rho Kinase ◽  
Artery Occlusion ◽  
Over Expression ◽  
Therapeutic Benefits ◽  
Infarction Volume ◽  
Photothrombotic Stroke

Background and Purpose: Sirt1 is a NAD+ dependent deacetylase that is known as one of important regulators for ischemic stroke. Because the role and mechanism of genetic sirt1 over-expression in ischemic brain injury has not yet been studied, we examined that brain-specific sirt1-overexpressing transgenic (BRASTO) mice might have significant beneficial effect in ischemic stroke through regulation of sirt1-Rho kinase (ROCK) signaling pathway. Methods: We induced a middle cerebral artery occlusion model in mice and tested the effect of resveratrol (100 mg/kg, i.p.) in ischemia/reperfusion (2h/22h) injury and tested the role and mechanism with BRASTO mice in photothrombotic stroke. Protein levels in mice brain tissue lysates were determined using western blotting. Results: Sirt1 activation by resveratrol treatment reduced infarction volume and improved neurological deficit score in transient focal cerebral ischemia. BRASTO mice did not show any obvious phenotypic abnormalities and BRASTO mice improved relative cerebral blood flow and reduced infarction volume by 68.4% compare to that of WT in photothrombotic stroke. Sirt1 over-expression in BRASTO mice was significantly increased by 4.2 fold higher than that of WT mice and Rho-kinase activity was significantly decreased by 54.6% in BRASTO mice. Conclusions: These findings indicate that neuronal specific sirt1 activation in BRASTO mice reduced infarction volume in photothrombotic stroke via down-regulation of ROCK signaling pathway. These results suggest that effect of neuronal sirt1 activation may have therapeutic benefits in ischemic stroke via ROCK signaling pathway.

scholarly journals Sirt1 Mediates Improvement in Cognitive Defects Induced by Focal Cerebral Ischemia Following Hyperbaric Oxygen Preconditioning in Rats

2017 ◽  
pp. 1029-1039 ◽  
Author(s):  
P. DING ◽  
D. REN ◽  
S. HE ◽  
M. HE ◽  
G. ZHANG ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Hyperbaric Oxygen ◽  
Cognitive Deficits ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Beneficial Effects ◽  
Mechanistic Basis ◽  
Hyperbaric Oxygen Preconditioning

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

scholarly journals Up-regulation of miR-499a-5p decreases cerebral ischemia/reperfusion injury by targeting PDCD4

2021 ◽  
Author(s):  
Weifeng Shan ◽  
Huifeng Ge ◽  
Bingquan Chen ◽  
Linger Huang ◽  
Shaojun Zhu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Cell Model ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Tunel Staining ◽  
Cerebral Ischemia Reperfusion

Abstract MiR-499a-5p was significantly down-regulated in degenerative tissues and correlated with apoptosis. Nonetheless, the biological function of miR-499a-5p in acute ischemic stroke has been still unclear. In this study, we found the plasma levels of miR-499a-5p were significantly down-regulated in 64 ischemic stroke patients and negatively correlated with the National Institutes of Health Stroke Scale score. Then, we constructed cerebral ischemia/reperfusion (I/R) injury in rats after middle cerebral artery occlusion and subsequent reperfusion and oxygen-glucose deprivation and reoxygenation (OGD/R) treated SH-SY5Y cell model. Transfection with miR-499a-5p mimic was accomplished by intracerebroventricular injection in the in vivo I/R injury model. We further found miR-499a-5p overexpression decreased infarct volumes and cell apoptosis in the in vivo I/R stroke model using TTC and TUNEL staining. PDCD4 was a direct target of miR-499a-5p by luciferase report assay and western blotting. Knockdown of PDCD4 reduced the infarct damage and cortical neuron apoptosis caused by I/R injury. MiR-499a-5p exerted neuroprotective roles mainly through inhibiting PDCD4-mediated apoptosis by CCK-8 assay, LDH release assay and flow cytometry analysis. These findings suggest that miR-499a-5p might represent a novel target that regulates brain injury by inhibiting PDCD4-mediating apoptosis.

Abstract T P229: Deletion of Voltage Gated Proton Channel in Microglial Cells is Neurovascular Protective After Ischemic Brain Injury

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Becca Ward ◽  
Mohammed Abdelsaid ◽  
Tianzheng Yu ◽  
Yisang Yoon ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Ischemia Reperfusion ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Proton Channel ◽  
Ros Generation ◽  
Vascular Integrity ◽  
Voltage Gated ◽  
Underlying Mechanisms ◽  
Cerebral Artery Occlusion

Despite the failure of antioxidant treatments in clinical trials, the undoubted role of reactive oxygen species (ROS) in neurovascular damage after ischemic stroke calls for a more targeted approach. ROS production by microglia, the primary resident immune cells in the brain, is a key event of this process in ischemic stroke. Voltage gated proton channel, Hv1, is localized primarily to microglia and sustains NADPH oxidase activity. Deletion of Hv1 is neuroprotective after permanent middle cerebral artery occlusion (MCAO). We hypothesized that Hv1-mediated microglial ROS generation is also critical for vascular integrity and contributes to reperfusion injury after transient ischemic stroke. The wildtype (WT) and Hv1 knockout (KO) rats (n=4) were subjected to permanent or 3/24 h transient MCAO. The neurological deficiency, infarct, hemorrhagic transformation, and edema ratio were assessed. We found that in both permanent and transient MCAO model, KO rats develop smaller infarct, less vascular injury, edema, and hemorrhagic transformation, resulting in better short-term functional outcome. These results suggest that deletion of microglial Hv1 channel is vasculoprotective after ischemia/reperfusion and the underlying mechanisms need to be further studied.

Therapeutic effects of different treatment periods against ischemic stroke and toxicology study of Angong Niuhuang Pill in rats

2020 ◽  
Author(s):  
Jianzhao Chen ◽  
Yushuang Chai ◽  
Yuanfeng He ◽  
Jisheng Huang ◽  
Ting Wan ◽  
...  
Keyword(s):  
Body Weight ◽  
Ischemic Stroke ◽  
Protective Effect ◽  
Toxic Effect ◽  
Treatment Period ◽  
Ischemia Reperfusion ◽  
Neurological Function ◽  
The Body ◽  
Therapeutic Effects ◽  
Toxicology Study

Abstract Background : Angong Niuhuang Pill (ANP) is one of the most famous drugs to treat stroke in China, but there is no definite treatment period in drug instruction. In this study, we used middle cerebral artery occlusion (MCAO) model to evaluate its therapeutic effects of different treatment periods and studied its toxic effect in rats. Methods : Protective effect of ANP was observed in the cerebral ischemia-reperfusion model in rats; ANP (270 mg/kg) three different treatment period included 1 day, 4 days and 7 days. The observation period was 30 days. Therapeutic effect was evaluated by detecting neurological function, cerebral infraction volume, brain histology and cytokines. Three dose including 550, 1640, 4910 mg/kg were studied in toxicology study. The administration period was 30 days. Toxic effect was evaluated by detecting appearance, behavior, excrement character, food-intake, body weight, hematological parameters and biomarkers such as TBA, GSTα, Cystatin C, clusterin, GSH, S-100B and MBP. Results : Seven days treatment period of ANP had better effect than 1 day and 4 days treatment periods in rat MCAO model from neurological function scores, the volume of cerebral infarction, brain histology and the serum content of IL-1β, TNF-α and NO; the brain content of IL-1β and NO. The results of 30 days multiple dose toxicology study showed no animal death in all groups; in ANP 4910 mg/kg group, the kidney and liver coefficient increased about 10%, the body weight grew more slowly, the TBA increased slightly. There was no abnormal change in histology. These all recovered after drug withdraw for 8 weeks. Conclusion: Seven days treatment period of ANP had more protective effect than 1 day and 4 days treatment periods in ischemic stroke rat. No observed adverse effect level (NOAEL) of ANP was 1640 mg/kg; the safety margin of ANP was 270-1640 mg/kg. These data provided reference to modify drug instruction.

scholarly journals Transcriptomic characterization of microglia activation in a rat model of ischemic stroke

2020 ◽  
Vol 40 (1_suppl) ◽  
pp. S34-S48
Author(s):  
Wenjun Deng ◽  
Emiri Mandeville ◽  
Yasukazu Terasaki ◽  
Wenlu Li ◽  
Julie Holder ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Phenotypic Diversity ◽  
Focal Cerebral Ischemia ◽  
Wide Spectrum ◽  
Spontaneously Hypertensive ◽  
Transient Focal Cerebral Ischemia ◽  
Microglial Response ◽  
Whole Transcriptome

Microglia are key regulators of inflammatory response after stroke and brain injury. To better understand activation of microglia as well as their phenotypic diversity after ischemic stroke, we profiled the transcriptome of microglia after 75 min transient focal cerebral ischemia in 3-month- and 12-month-old male spontaneously hypertensive rats. Microglia were isolated from the brains by FACS sorting on days 3 and 14 after cerebral ischemia. GeneChip Rat 1.0ST microarray was used to profile the whole transcriptome of sorted microglia. We identified an evolving and complex pattern of activation from 3 to 14 days after stroke onset. M2-like patterns were extensively and persistently upregulated over time. M1-like patterns were only mildly upregulated, mostly at day 14. Younger 3-month-old brains showed a larger microglial response in both pro- and anti-inflammatory pathways, compared to older 12-month-old brains. Importantly, our data revealed that after stroke, most microglia are activated towards a wide spectrum of novel polarization states beyond the standard M1/M2 dichotomy, especially in pathways related to TLR2 and dietary fatty acid signaling. Finally, classes of transcription factors that might potentially regulate microglial activation were identified. These findings should provide a comprehensive database for dissecting microglial mechanisms and pursuing neuroinflammation targets for acute ischemic stroke.

scholarly journals Chronic Unexpected Mild Stress Destroys Synaptic Plasticity of Neurons through a Glutamate Transporter, GLT-1, of Astrocytes in the Ischemic Stroke Rat

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Dafan Yu ◽  
Zhenxing Cheng ◽  
Abdoulaye Idriss Ali ◽  
Jiamin Wang ◽  
Kai Le ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Synaptic Plasticity ◽  
Dentate Gyrus ◽  
Average Distance ◽  
Glutamate Transporter ◽  
Synaptic Cleft ◽  
Mild Stress ◽  
Poststroke Depression ◽  
Transmission Electron ◽  
Synaptic Formation

Background and Objective. Chronic unexpected mild stress (CUMS) destroys synaptic plasticity of hippocampal regenerated neurons that may be involved in the occurrence of poststroke depression. Astrocytes uptake glutamate at the synapse and provide metabolic support for neighboring neurons. Currently, we aim to investigate whether CUMS inhibits synaptic formation of regenerated neurons through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rats. Method. We exposed the ischemic stroke rats to ceftriaxone, during the CUMS intervention period to determine the effects of GLT-1 on glutamate circulation by immunofluorescence and mass spectrometry and its influences to synaptic plasticity by western blot and transmission electron microscopy. Result. CUMS evidently reduced the level of astroglial GLT-1 in the hippocampus of the ischemic rats (p<0.05), resulting in smaller amount of glutamate being transported into astrocytes surrounding synapses (p<0.05), and then expression of synaptophysin was suppressed (p<0.05) in hippocampal dentate gyrus. The ultrastructures of synapses in dentate gyrus were adversely influenced including decreased proportion of smile synapses, shortened thickness of postsynaptic density, reduced number of vesicles, and widened average distance of the synaptic cleft (all p<0.05). Moreover, ceftriaxone can promote glutamate circulation and synaptic plasticity (all p<0.05) by raising astroglial GLT-1 (p<0.05) and then improve depressive behaviors of the CUMS-induced model rats (p<0.05). Conclusion. Our study shows that CUMS destroys synaptic plasticity of regenerated neurons in the hippocampus through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rats. This may indicate one potential pathogenesis of poststroke depression.

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