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Telaprevir Improves Memory and Cognition in Mice Suffering Ischemic Stroke via Targeting MALT1-Mediated Calcium
Yi-Yue Zhang1,2, Jing-Jie Peng3, Di Chen1,2
1Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
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 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.
Insights
Telaprevir, a MALT1 inhibitor, protects against ischemic stroke brain injury by reducing excitotoxicity and necroptosis. This drug improved survival and cognitive function in stroke mice, suggesting a potential new treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Cellular Biology
Background:
- Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) drives brain injury in ischemic stroke through excitotoxicity and necroptosis.
- Telaprevir, a hepatitis C virus protease inhibitor, shows potential as a MALT1 inhibitor.
Purpose of the Study:
- To investigate the neuroprotective effects of telaprevir in ischemic stroke by targeting MALT1.
- To elucidate the mechanisms underlying telaprevir's action on excitotoxicity, calcium overload, and necroptosis.
Main Methods:
- Utilized an in vivo mouse model of ischemic stroke and in vitro hypoxia-treated nerve cells.
- Assessed infarct volume, survival rates, sensorimotor, memory, and cognitive functions.
- Analyzed intracellular calcium concentrations, LDH release, and levels of MALT1, GluN2B, STEP61, and necroptosis-associated proteins (RIPK1/RIPK3/MLKL).
Main Results:
- Telaprevir significantly reduced infarct volume and improved long-term survival and functional outcomes in stroke mice.
- In vitro, telaprevir decreased intracellular calcium and LDH release.
- Telaprevir inhibited MALT1 protease activity, reducing GluN2B membrane levels and phosphorylation, and suppressing the RIPK1/RIPK3/MLKL necroptosis pathway.
Conclusions:
- Telaprevir demonstrates neuroprotective effects against cerebral ischemic injury by inhibiting MALT1.
- The drug alleviates neuronal damage by preventing GluN2B activation, limiting calcium overload, and suppressing necroptosis.
- Telaprevir represents a potential therapeutic candidate for treating ischemic stroke.
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