Ruxolitinib Ameliorates Neuronal Pyroptosis in the Acute Phase of Intracerebral Hemorrhage through Inhibiting the Activation of Caspase-8

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Intracerebral hemorrhage (ICH) is a common type of stroke with higher rates of death and neurological dysfunction than ischemic stroke. Based on previous studies, we found that reducing neuronal pyroptosis in the acute phase of ICH improved the neurological dysfunction of mice that suffered from nontraumatic parenchymal hemorrhage. Still, the mechanism must be further explored. In this study, we used ruxolitinib, a selective inhibitor of JAK1/2, to treat CD-1 mice with ICH. We found that inhibition of the JAK1/STAT1 pathway alleviated ICH-induced neuronal pyroptosis and that the activation of caspase-8 was suppressed at the same time. Given that caspase-8 is crosstalk for different types of programmed cell death and its role in the pyroptotic cell death after ICH has not yet been defined, we administered z-IETD-fmk, a selective inhibitor of caspase-8, to treat mice with ICH. We found that the downregulation of caspase-8 reversed ICH-induced neuronal pyroptosis and improved motor and cognitive functions of mice after ICH. Our results show that the JAK1/STAT1/caspase-8 axis is a critical mediator of neuronal pyroptosis in ICH. Inhibiting this axis improved neurological outcomes of mice with ICH, and we propose ruxolitinib as a potential therapeutic approach for post-ICH treatment.

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