DS-10 mitigates cerebral ischemia-reperfusion injury in mice through suppressing caspase-1-mediated pyroptosis.

Abstract

Ischemic stroke (IS) is an acute cerebrovascular event with substantial mortality and morbidity, yet effective therapies are lacking. This study investigates the protective properties of DS-10, a decapeptide from Dunaliella salina, against cerebral ischemia-reperfusion injury (CIRI). Using a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated BV2 microglial cells, we evaluated the effects of DS-10. In vivo, DS-10 treatment significantly improved neurological motor impairments, decreased cerebral infarction volume, and reduced histological damage in MCAO/R mice. Network pharmacology analysis identified 54 overlapping potential targets. Molecular docking, drug affinity responsive target stability (DARTS), and cellular thermal shift assay (CETSA) analyses convergently indicated a direct interaction between DS-10 and cysteine-aspartic protease-1 (caspase-1). Moreover, DS-10 treatment markedly reduced caspase-1 enzymatic activity and ameliorated characteristic pyroptotic features in microglia as visualized by transmission electron microscopy (TEM) in the peri-infarct cortex. Consistently, DS-10 suppressed pyroptosis-related mediators at both transcriptional and protein levels in vivo and in vitro. Notably, siRNA-mediated knockdown of caspase-1 abolished the protective effects of DS-10 on pyroptotic markers, demonstrating that the anti-pyroptotic action of DS-10 is strictly dependent on caspase-1. This study provides novel evidence that the neuroprotective effect of DS-10 against IS is through inhibiting caspase-1-mediated pyroptosis. These findings highlight potential therapeutic targets for modulating pyroptosis in IS.