Curculigoside attenuates cerebral ischemia-reperfusion injury via TRPM2-mediated microglial polarization

Objective Cerebral ischemia-reperfusion injury (CIRI) remains a major challenge in clinical practice, without effective and targeted approaches to address it. Curculigoside has been reported to exert beneficial effects in CIRI, yet the underlying novel mechanisms remain unclear. In this work, we aimed to explore whether Curculigoside exerted its protective role by regulating transient receptor potential melastatin 2 (TRPM2)-mediated microglial polarization. Methods A well-established middle cerebral artery occlusion (MCAO) model was constructed in Sprague-Dawley rats, with Curculigoside administrated via the caudal vein. In vitro, LPS/IFN-γ-stimulated BV2 microglial cells were used to investigate the effects of Curculigoside on polarization and neuroinflammation. High-throughput mRNA sequencing was used to predict key targets of Curculigoside. TRPM2 overexpression and autophagy inhibition assays were conducted to verify the underlying mechanism. Results Curculigoside treatment significantly alleviated neurological deficits, reduced cerebral infarction volume, and decreased brain edema, accompanied by inhibited M1 polarization of microglia and mitigated inflammatory injury during CIRI. Curculigoside reduced pro-inflammatory M1 polarization in LPS/IFN-γ–stimulated BV2 microglia, thereby reducing neuronal apoptosis. RNA-seq functional enrichment analysis identified TRPM2 as a key target, and Curculigoside was found to downregulate TRPM2 expression and regulate the mTOR-mediated autophagy pathway. Notably, the protective effects of Curculigoside on microglial polarization were reversed by TRPM2 overexpression or autophagy inhibition. Conclusion Curculigoside mitigates CIRI by promoting beneficial microglial polarization through the TRPM2/mTOR-autophagy axis, supporting its potential as a therapeutic agent for CIRI.