Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
ACS Chem Neurosci. 2023 Sep 6;14(17):3113-3124. doi: 10.1021/acschemneuro.3c00250. Epub 2023 Aug 9.
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) has been confirmed to contribute to brain injury in ischemic stroke via promoting excitotoxicity and necroptosis. Telaprevir, a hepatitis C virus protease inhibitor, is predicted to be a potential MALT1 inhibitor. Here, we showed that telaprevir protected against cerebral ischemic injury via inhibiting MALT1, thereby preventing glutamate receptor ionotropic NMDA 2B (GluN2B) activation, limiting calcium overload, and suppressing necroptosis. In ischemic stroke mice, telaprevir reduced infarct volume, improved the long-term survival rate, and enhanced sensorimotor, memory, and cognitive functions. In hypoxia-treated nerve cells, telaprevir decreased the intracellular calcium concentrations and reduced LDH release. Mechanistically, telaprevir inhibited MALT1 protease activity, thus decreasing the membrane protein level of GluN2B and its phosphorylation through reducing the level of STEP61. Moreover, telaprevir was able to inhibit the levels of necroptosis-associated proteins. According to these results, it can be concluded that telaprevir alleviates neuronal brain injury in stroke mice via restraining GluN2B activation and suppresses the receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway through inhibiting MALT1. Thus, telaprevir might have a novel indication for treating patients with ischemic stroke.
黏膜相关淋巴组织淋巴瘤易位蛋白 1（MALT1）已被证实通过促进兴奋性毒性和坏死性凋亡来促进缺血性中风中的脑损伤。特拉普韦是一种丙型肝炎病毒蛋白酶抑制剂，被预测为潜在的 MALT1 抑制剂。在这里，我们表明特拉普韦通过抑制 MALT1 来保护大脑免受缺血性损伤，从而防止谷氨酸受体离子型 NMDA 2B（GluN2B）激活、限制钙超载和抑制坏死性凋亡。在缺血性中风小鼠中，特拉普韦减少梗死体积，提高长期存活率，并增强感觉运动、记忆和认知功能。在缺氧处理的神经细胞中，特拉普韦降低细胞内钙浓度并减少 LDH 释放。在机制上，特拉普韦抑制 MALT1 蛋白酶活性，从而通过降低 STEP61 的水平来减少 GluN2B 的膜蛋白水平及其磷酸化。此外，特拉普韦能够抑制坏死性凋亡相关蛋白的水平。根据这些结果，可以得出结论，特拉普韦通过抑制 GluN2B 激活来减轻中风小鼠的神经元脑损伤，并通过抑制 MALT1 来抑制受体相互作用蛋白激酶 1（RIPK1）/受体相互作用蛋白激酶 3（RIPK3）/混合谱系激酶结构域样假激酶（MLKL）通路。因此，特拉普韦可能为治疗缺血性中风患者提供新的治疗靶点。
