Inhibition of extracellular signal-regulated kinase/calpain-2 pathway reduces neuroinflammation and necroptosis after cerebral ischemia-reperfusion injury in a rat model of cardiac arrest
| Autor: | Xin-Yue Tian, Zhi-Jiang Wu, Nuo Li, Ye-Gui Yang, Meng-Hua Chen, Lu Xie, Wen-Yan Wang, Xin-Sen Zou, Gao-Yang Zhao |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway Necroptosis Immunology Pharmacology Brain Ischemia Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine medicine Animals Immunology and Allergy Extracellular Signal-Regulated MAP Kinases Neuroinflammation Flavonoids Inflammation Microglia biology Calpain Kinase business.industry Dipeptides medicine.disease Heart Arrest Disease Models Animal 030104 developmental biology medicine.anatomical_structure Reperfusion Injury 030220 oncology & carcinogenesis biology.protein Signal transduction business Reperfusion injury Signal Transduction |
| Zdroj: | International Immunopharmacology. 93:107377 |
| ISSN: | 1567-5769 |
| DOI: | 10.1016/j.intimp.2021.107377 |
| Popis: | Background Cerebral ischemia–reperfusion injury (CIRI) is the leading cause of poor neurological prognosis after cardiopulmonary resuscitation (CPR). We previously reported that the extracellular signal-regulated kinase (ERK) activation mediates CIRI. Here, we explored the potential ERK/calpain-2 pathway role in CIRI using a rat model of cardiac arrest (CA). Methods Adult male Sprague-Dawley rats suffered from CA/CPR-induced CIRI, received saline, DMSO, PD98059 (ERK1/2 inhibitor, 0.3 mg/kg), or MDL28170 (calpain inhibitor, 3.0 mg/kg) after spontaneous circulation recovery. The survival rate and the neurological deficit score (NDS) were utilized to assess the brain function. Hematoxylin stain, Nissl staining, and transmission electron microscopy were used to evaluate the neuron injury. The expression levels of p-ERK, ERK, calpain-2, neuroinflammation-related markers (GFAP, Iba1, IL-1β, TNF-α), and necroptosis proteins (TNFR1, RIPK1, RIPK3, p-MLKL, and MLKL) in the brain tissues were determined by western blotting and immunohistochemistry. Fluorescent multiplex immunohistochemistry was used to analyze the p-ERK, calpain-2, and RIPK3 co-expression in neurons, and RIPK3 expression levels in microglia or astrocytes. Results At 24 h after CA/CPR, the rats in the saline-treated and DMSO groups presented with injury tissue morphology, low NDS, ERK/calpain-2 pathway activation, and inflammatory cytokine and necroptosis protein over-expression in the brain tissue. After PD98059 and MDL28170 treatment, the brain function was improved, while inflammatory response and necroptosis were suppressed by ERK/calpain-2 pathway inhibition. Conclusion Inflammation activation and necroptosis involved in CA/CPR-induced CIRI were regulated by the ERK/calpain-2 signaling pathway. Inhibition of that pathway can reduce neuroinflammation and necroptosis after CIRI in the CA model rats. |
| Databáze: | OpenAIRE |
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