GFH312 Reduces Neuronal Death by Inhibiting RIPK1-Mediated Apoptosis and Necroptosis After Ischemic Stroke.

IF 6.6 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2026-10-01 DOI:10.1002/cns.71053

Ze Liu, Shengju Wu, Qian Suo, Chang Liu, Rubing Shi, Jing Ye, Haroon Khan, Jing-Yang Zhang, Yaohui Tang, Zhijun Zhang, Wanlu Li, Fu-Sheng Zhou, Guo-Yuan Yang

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引用次数: 0

Abstract

Aims: To investigate the role of the RIPK1 inhibitor GFH312 in ischemic stroke and identify its potential mechanisms.

Methods: GFH312 was administered to adult mice in an ischemic stroke model. To ascertain the effectiveness of treatment, neurobehavioral tests and assessments of brain damage were carried out. Brain tissues were examined using immunofluorescence as well as western blot and real-time quantitative PCR at various intervals following ischemia to evaluate inflammatory gene expression and signaling pathways linked to apoptosis and necroptosis.

Results: Temporal analysis revealed that necroptosis and apoptosis were rapidly activated following ischemia, peaking at 1-3 days. GFH312 significantly improved neurological function and reduced brain injury in stroke mice. Mechanistically, GFH312 markedly inhibited apoptosis and necroptosis via suppression of the RIPK1-related signaling pathway (RIPK1-RIPK3-MLKL). In addition, GFH312 greatly decreased inflammatory gene expression in the brain.

Conclusion: Apoptosis and necrotic apoptosis occur primarily during the acute poststroke phase. GFH312 exerts neuroprotective effects after ischemic stroke, which are associated with suppression of RIPK1-related apoptosis, necroptosis, and neuroinflammation.

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GFH312通过抑制ripk1介导的缺血性脑卒中后神经元凋亡和坏死凋亡减少神经元死亡。

目的：探讨RIPK1抑制剂GFH312在缺血性脑卒中中的作用及其潜在机制。方法：对缺血性脑卒中模型成年小鼠给予GFH312。为了确定治疗的有效性，进行了神经行为测试和脑损伤评估。在缺血后的不同时间间隔，采用免疫荧光、western blot和实时定量PCR检测脑组织，以评估与细胞凋亡和坏死下垂相关的炎症基因表达和信号通路。结果：时间分析显示缺血后坏死下垂和细胞凋亡迅速激活，在1-3天达到峰值。GFH312显著改善脑卒中小鼠的神经功能，减少脑损伤。机制上，GFH312通过抑制ripk1相关信号通路（RIPK1-RIPK3-MLKL）显著抑制细胞凋亡和坏死。此外，GFH312显著降低了脑内炎症基因的表达。结论：细胞凋亡和坏死细胞凋亡主要发生在脑卒中后急性期。GFH312在缺血性脑卒中后发挥神经保护作用，其作用机制与抑制ripk1相关的细胞凋亡、坏死和神经炎症有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.