White matter injury (WMI) caused by intracerebral hemorrhage (ICH) is a major neuropathological feature closely associated with neurological impairments. Oligodendrocytes (OLs), responsible for repairing WMI, undergo cell death induced by hematoma compression and secondary neuroinflammation following ICH. Sephin1, a selective inhibitor of PPP1R15A, has been shown to reduce general protein synthesis and protect OLs by prolonging the integrated stress response (ISR). We aimed to evaluate the effectiveness of Sephin1 in protecting OLs in experimental ICH mice and primary OLs. Herein, we evaluated the performance of neurological deficits and WMI in ICH mice treated with Sephin1 or vehicle. Moreover, we labeled and tracked apoptotic, proliferating, and mature OLs using immunofluorescence staining. We found that Sephin1 improved long-term neurological function in ICH mice, which was accompanied by a significant alleviation of WMI in the perihematomal region. Our data also indicated that Sephin1 dramatically increased the population of OLs in the perihematomal region after ICH. Additionally, Sephin1 attenuated neuroinflammation after ICH by inhibiting microglial polarization to the pro-inflammatory phenotype. Together, our observations suggest that Sephin1 is a promising therapeutic drug to alleviate WMI in ICH patients, highlighting its translational potential to improve neurological recovery in hemorrhagic stroke.
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