Telaprevir improves memory and cognition in mice suffered ischemic stroke via targeting MALT1-mediated calcium overload and necroptosis

【作者】 张议月； 彭靖杰； 陈迪； 刘惠棋； 姚碧凤； 彭军； 罗秀菊；

【机构】 中南大学湘雅药学院药理学系,心血管研究湖南省重点实验室； 中南大学湘雅三医院检验科；

【摘要】 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 nerves cells,Telaprevir decreased the intracellular calcium concentrations and reduced LDH release.Mechanistically,Telaprevir inhibited MALT1 protease activity,thus decreased 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 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.更多还原

【Abstract】 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 nerves cells,Telaprevir decreased the intracellular calcium concentrations and reduced LDH release.Mechanistically,Telaprevir inhibited MALT1 protease activity,thus decreased 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 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.更多还原