scholarly journals Contribution of TRPC Channels in Neuronal Excitotoxicity Associated With Neurodegenerative Disease and Ischemic Stroke

2021 ◽  
Vol 8 ◽  
Author(s):  
Jaepyo Jeon ◽  
Fan Bu ◽  
Guanghua Sun ◽  
Jin-Bin Tian ◽  
Shun-Ming Ting ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Neurodegenerative Diseases ◽  
Glutamate Receptors ◽  
Neuronal Death ◽  
Metabotropic Glutamate Receptors ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion ◽  
Trpc Channels ◽  
Cerebral Ischemia Reperfusion

The seven canonical members of transient receptor potential (TRPC) proteins form cation channels that evoke membrane depolarization and intracellular calcium concentration ([Ca2+]i) rise, which are not only important for regulating cell function but their deregulation can also lead to cell damage. Recent studies have implicated complex roles of TRPC channels in neurodegenerative diseases including ischemic stroke. Brain ischemia reduces oxygen and glucose supply to neurons, i.e., Oxygen and Glucose Deprivation (OGD), resulting in [Ca2+]i elevation, ion dyshomeostasis, and excitotoxicity, which are also common in many forms of neurodegenerative diseases. Although ionotropic glutamate receptors, e.g., N-methyl-D-aspartate receptors, are well established to play roles in excitotoxicity, the contribution of metabotropic glutamate receptors and their downstream effectors, i.e., TRPC channels, should not be neglected. Here, we summarize the current findings about contributions of TRPC channels in neurodegenerative diseases, with a focus on OGD-induced neuronal death and rodent models of cerebral ischemia/reperfusion. TRPC channels play both detrimental and protective roles to neurodegeneration depending on the TRPC subtype and specific pathological conditions involved. When illustrated the mechanisms by which TRPC channels are involved in neuronal survival or death seem differ greatly, implicating diverse and complex regulation. We provide our own data showing that TRPC1/C4/C5, especially TRPC4, may be generally detrimental in OGD and cerebral ischemia/reperfusion. We propose that although TRPC channels significantly contribute to ischemic neuronal death, detailed mechanisms and specific roles of TRPC subtypes in brain injury at different stages of ischemia/reperfusion and in different brain regions need to be carefully and systematically investigated.

scholarly journals Senolytic Therapy for Cerebral Ischemia-Reperfusion Injury

2021 ◽  
Vol 22 (21) ◽  
pp. 11967
Author(s):  
Songhyun Lim ◽  
Tae Jung Kim ◽  
Young-Ju Kim ◽  
Cheesue Kim ◽  
Sang-Bae Ko ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Inflammatory Cytokines ◽  
Cellular Senescence ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
Severe Disabilities ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ir Injury

Ischemic stroke is one of the leading causes of death, and even timely treatment can result in severe disabilities. Reperfusion of the ischemic stroke region and restoration of the blood supply often lead to a series of cellular and biochemical consequences, including generation of reactive oxygen species (ROS), expression of inflammatory cytokines, inflammation, and cerebral cell damage, which is collectively called cerebral ischemia-reperfusion (IR) injury. Since ROS and inflammatory cytokines are involved in cerebral IR injury, injury could involve cellular senescence. Thus, we investigated whether senolytic therapy that eliminates senescent cells could be an effective treatment for cerebral IR injury. To determine whether IR induces neural cell senescence in vitro, astrocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced astrocyte senescence and senescent cells in OGD/R-injured astrocytes were effectively eliminated in vitro by ABT263, a senolytic agent. IR in rats with intraluminal middle cerebral artery occlusion induced cellular senescence in the ischemic region. The senescent cells in IR-injured rats were effectively eliminated by intravenous injections of ABT263. Importantly, ABT263 treatment significantly reduced the infarct volume and improved neurological function in behavioral tests. This study demonstrated, for the first time, that senolytic therapy has therapeutic potential for cerebral IR injury.

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.

scholarly journals Effects of the Insulted Neuronal Cells-Derived Extracellular Vesicles on the Survival of Umbilical Cord-Derived Mesenchymal Stem Cells following Cerebral Ischemia/Reperfusion Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-26
Author(s):  
Yan Huang ◽  
Zuo Liu ◽  
Fengbo Tan ◽  
Zhiping Hu ◽  
Ming Lu
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Umbilical Cord ◽  
Ischemia Reperfusion ◽  
Neuronal Cells ◽  
Cerebral Ischemia Reperfusion ◽  
N2a Cells ◽  
Hypoxia Preconditioning

Umbilical cord-derived mesenchymal stem cells (UC-MSCs) engraftment is a potential therapy for cerebral ischemic stroke. However, the harsh microenvironment induced by cerebral ischemia/reperfusion restricts the survival rate and therapeutic efficiency of the engrafted UC-MSCs. In this study, we explored whether small extracellular vesicles (EVs) derived from injured neuronal cells following exposure to cerebral ischemia/reperfusion insult affect the survival of transplanted UC-MSCs. To establish a simulation of cerebral ischemia/reperfusion microenvironment comprising engrafted UC-MSCs and neuronal cells, we cocultured EVs derived from injured N2A cells, caused by exposure to oxygen-glucose deprivation and reperfusion (OGD/R) insult, with UC-MSCs in a conditioned medium. Coculture of UC-MSCs with EVs exacerbated the OGD/R-induced apoptosis and oxidative stress. Suppression of EVs-release via knock-down of Rab27a effectively protected the UC-MSCs from OGD/R-induced insult. Moreover, hypoxia preconditioning not only elevated the survival of UC-MSCs but also improved the paracrine mechanism of injured N2A cells. Altogether, these results show that EVs from injured N2A cells exacerbates OGD/R-induced injury on transplanted UC-MSCs in vitro. Hypoxia preconditioning enhances the survival of the engrafted-UC-MSCs; hence, thus could be an effective approach for improving UC-MSCs therapy in ischemic stroke.

scholarly journals OM-MSCs Alleviate the Golgi Apparatus Stress Response following Cerebral Ischemia/Reperfusion Injury via the PEDF-PI3K/Akt/mTOR Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Jialin He ◽  
Jianyang Liu ◽  
Yan Huang ◽  
Xiangqi Tang ◽  
Han Xiao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Stress Response ◽  
Cerebral Ischemia ◽  
Stress Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

The mechanism of Golgi apparatus (GA) stress responses mediated by GOLPH3 has been widely studied in ischemic stroke, and the neuroprotection effect of olfactory mucosa mesenchymal stem cells (OM-MSCs) against cerebral ischemia/reperfusion injury (IRI) has been preliminarily presented. However, the exact role of OM-MSCs in the GA stress response following cerebral IRI remains to be elucidated. In the present study, we used an oxygen-glucose deprivation/reoxygenation (OGD/R) model and reversible middle cerebral artery occlusion (MCAO) model to simulate cerebral IRI in vitro and in vivo. Our results showed that the level of GOLPH3 protein, reactive oxygen species (ROS), and Ca2+ was upregulated, SPCA1 level was downregulated, and GA fragmentation was increased in ischemic stroke models, and OM-MSC treatment clearly ameliorated these GA stress responses in vitro and in vivo. Subsequently, the knockdown of PEDF in OM-MSCs using PEDF-specific siRNA further demonstrated that secretion of PEDF in OM-MSCs protected OGD/R-treated N2a cells and MCAO rats from GA stress response. Additionally, rescue experiment using specific pathway inhibitors suggested that OM-MSCs could promote the phosphorylation of the PI3K/Akt/mTOR pathway, thereby mitigating OGD/R-induced GA stress response and excessive autophagy. In conclusion, OM-MSCs minimized the GA stress response following cerebral IRI, at least partially, through the PEDF-PI3K/Akt/mTOR pathway.

scholarly journals Transient Receptor Potential Canonical 5-Scramblase Signaling Complex Mediates Neuronal Phosphatidylserine Externalization and Apoptosis

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 547 ◽  
Author(s):  
Jizheng Guo ◽  
Jie Li ◽  
Lin Xia ◽  
Yang Wang ◽  
Jinhang Zhu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Cortical Neurons ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion ◽  
Receptor Potential ◽  
Hek293 Cells ◽  
Wild Type ◽  
Signaling Complex ◽  
Cerebral Ischemia Reperfusion ◽  
Transient Receptor

Phospholipid scramblase 1 (PLSCR1), a lipid-binding and Ca2+-sensitive protein located on plasma membranes, is critically involved in phosphatidylserine (PS) externalization, an important process in cell apoptosis. Transient receptor potential canonical 5 (TRPC5), is a nonselective Ca2+ channel in neurons that interacts with many downstream molecules, participating in diverse physiological functions including temperature or mechanical sensation. The interaction between TRPC5 and PLSCR1 has never been reported. Here, we showed that PLSCR1 interacts with TRPC5 through their C-termini in HEK293 cells and mouse cortical neurons. Formation of TRPC5-PLSCR1 complex stimulates PS externalization and promotes cell apoptosis in HEK293 cells and mouse cerebral neurons. Furthermore, in vivo studies showed that PS externalization in cortical neurons induced by artificial cerebral ischemia-reperfusion was reduced in TRPC5 knockout mice compared to wild-type mice, and that the percentage of apoptotic neurons was also lower in TRPC5 knockout mice than in wild-type mice. Collectively, the present study suggested that TRPC5-PLSCR1 is a signaling complex mediating PS externalization and apoptosis in neurons and that TRPC5 plays a pathological role in cerebral-ischemia reperfusion injury.

scholarly journals Pien-Tze-Huang attenuates neuroinflammation in cerebral ischemia-reperfusion injury in rats partially through the TLR4/NF-κB/MAPK pathway

2021 ◽  
Author(s):  
Xiao-qin Zhang ◽  
Qing Zhang ◽  
Li-li Huang ◽  
Ming-zhen Liu ◽  
Zai-xing Cheng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion ◽  
Protein Expressions ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Pien Tze Huang ◽  
Anti Inflammatory

Abstract Background Pien-Tze-Huang (PTH), one of the most famous traditional Chinese medicines in China, is traditionally applied to treat various inflammation-related diseases including stroke. However, literature regarding the anti-inflammatory effects and possible mechanisms of PTH in ischemic stroke is unavailable. This study intended to investigate the anti-inflammatory effects of PTH against cerebral ischemia-reperfusion injury and clarify its potential molecular mechanisms. Methods Cerebral ischemia-reperfusion injury was induced through transient left transient middle cerebral artery occlusion (MCAO) in male rats receiving oral pretreatment with PTH (180 mg/kg) for 4 days. TLR4 antagonist TAK-242 (3 mg/kg) was injected intraperitoneally at 1.5 h after MCAO. Magnetic resonance imaging, hematoxylin–eosin staining, RT-PCR, western blot, and immunofluorescence methods were used to studied the effect and mechanism of PTH against ischemic stroke. Results PTH treatment reduced cerebral infarct volume, improved neurological function, and ameliorated brain histopathological damage in MCAO rats. In addition, it markedly suppressed a variety of inflammatory responses as evidenced by the reduced mRNA levels of IL-1β, IL-6, TNF-α and MCP-1; the inhibition of microglia and astrocyte activations; and the decreased protein expressions of iNOS and COX-2 in injured brains. Moreover, PTH down-regulated the protein expressions of TLR4, MyD88, and TRAF6; reduced the expression and NF-κB; and lowered the protein expressions of p-ERK1/2, p-JNK, and p-p38. Similar effects were observed in the TAK-242 treated group. However, TAK-242 did not significantly reinforce the anti-inflammatory effects of PTH. Conclusion PTH could attenuate neuroinflammation, improve neurological function, and alleviate brain injury in MCAO rats, and its potential mechanisms are partly connected to inhibition of neuroinflammation involving the TLR4/NF-κB/MAPK signaling pathway.

Abstract T P84: Neuroprotective Effect of Probenecid in a Rat Model of Transient Global Cerebral Ischemia-Reperfusion

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Rui-li Wei ◽  
Yan Xu ◽  
Jing-ye Wang ◽  
Ben-yan Luo
Keyword(s):  
Cerebral Ischemia ◽  
Protective Effect ◽  
Neuronal Death ◽  
Ischemia Reperfusion ◽  
Cerebral Injury ◽  
Therapeutic Drug ◽  
Ca1 Region ◽  
Cerebral Ischemia Reperfusion ◽  
Hippocampal Ca1

Background and Purpose: Probenecid (PROB) has been used for decades to treat gouty arthritis with few side effects and recent studies revealed that it is also a specific inhibitor of pannexin-1 channel. Panx1 channel was activated by ischemic injury and inhibition of the panx1 channel maybe efficacious in stroke treatment. However, the role of PROB in cerebral ischemia /reperfusion (I/R) injury remains unclear. The aim of this study was to investigate the role of PROB in the transient global cerebral I/R injury in rats and its protective mechanisms. Methods: Twenty minutes of transient global cerebral I/R was induced using the four-vessel occlusion (4-VO) method in rats. PROB was given in the different dose, time and administration routes to verify its neuroprotective effects. Neuronal death in the hippocampal CA1 region was observed using H & E staining 7 days after ischemia. Molecular mechanisms of activation of calpain-cathepsin pathway and inflammatory cells by I/R injury were also investigated. Results: Treatment with PROB (0.1, 1 and 10 mg/kg ) 10 min before ischemia protected against I/R-induced hippocampal CA1 neuronal death significantly, and 1 mg/kg has best protective effect. Post-insult treatment 2h after reperfusion also protected against neuronal death and prolonged use for continuous 7 days could improve its protective effects compared to the single use 6h after reperfusion.Furthermore,oral administration also had protective effect. Cathepsin B expression was inceased significantly in CA-1 region after ischemia and PROB treatment could inhibit its expression. Expression of both calpain-1 and hsp70 at 1d ,2d and 3d after reperfusion were upregulated, whereas the expression of calpain-1 was inhibited and hsp70 was strengthened by pre-treatment with PROB. Prolonged PROB treatment suppressed the activation of microglia and astrocytes, reduced the number of microglia in CA1 region. Conclusions: Our study indicates that PROB protects against transient global cerebral I/R injury administrated before ischemia and even 6h after reperfusion by reducing calpain-1 expression , inhibiting lysosomal rupture and the activation of the glia, which suggests RPOB may be a promising therapeutic drug for clinical treatment of ischemic cerebral injury.

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