Telaprevir Improves Memory and Cognition in Mice Suffering Ischemic Stroke via Targeting MALT1-Mediated Calcium Overload and Necroptosis

Mucosa-associated lymphoid tissue lymphoma translocationprotein1 (MALT1) has been confirmed to contribute to brain injury in ischemicstroke via promoting excitotoxicity and necroptosis. Telaprevir, ahepatitis C virus protease inhibitor, is predicted to be a potentialMALT1 inhibitor. Here, we showed that telaprevir protected againstcerebral ischemic injury via inhibiting MALT1, thereby preventingglutamate receptor ionotropic NMDA 2B (GluN2B) activation, limitingcalcium overload, and suppressing necroptosis. In ischemic strokemice, telaprevir reduced infarct volume, improved the long-term survivalrate, and enhanced sensorimotor, memory, and cognitive functions.In hypoxia-treated nerve cells, telaprevir decreased the intracellularcalcium concentrations and reduced LDH release. Mechanistically, telaprevirinhibited MALT1 protease activity, thus decreasing the membrane proteinlevel of GluN2B and its phosphorylation through reducing the levelof STEP61. Moreover, telaprevir was able to inhibit the levels ofnecroptosis-associated proteins. According to these results, it canbe concluded that telaprevir alleviates neuronal brain injury in strokemice via restraining GluN2B activation and suppresses the receptor-interactingprotein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixedlineage kinase domain-like pseudokinase (MLKL) pathway through inhibitingMALT1. Thus, telaprevir might have a novel indication for treatingpatients with ischemic stroke.

Automated summary

Telaprevir, a hepatitis C virus protease inhibitor, can protect against cerebral ischemic injury by inhibiting MALT1 and reducing calcium overload in nerve cells. It also reduces the activation of GluN2B and necroptosis-associated proteins.