Neuroprotective effects of sinomenine and metformin in diabetic stroke: Role of NLRP3/caspase‐1 and mitophagy

Type 2 diabetes mellitus (T2DM) significantly increases the risk and severity of cerebral ischaemia–reperfusion (IR) injury, yet effective neuroprotective treatments for diabetic stroke remain limited. This study explored whether a combination of sinomenine and metformin could offer enhanced neuroprotection in diabetic rats subjected to cerebral IR injury, and investigated the molecular pathways involved. Male rats were rendered diabetic using a high‐fat diet and low‐dose streptozotocin. After establishing diabetes, rats underwent transient middle cerebral artery occlusion followed by 24 h of reperfusion. Animals received sinomenine, metformin, or their combination for 7 days prior to IR induction. Neurological function was assessed using standardized behavioural tests. Molecular analyses measured markers of pyroptosis (NLRP3, cleaved caspase‐1, gasdermin D N‐terminal fragment), mitophagy (PTEN‐induced kinase 1 (PINK‐1), Parkin), inflammation (interleukin (IL)‐1β, IL‐18) and oxidative stress (malondialdehyde, superoxide dismutase, glutathione peroxidase). To determine the role of mitophagy, a subset of animals was pretreated with the mitophagy inhibitor mitochondrial division inhibitor 1 (Mdv‐1). Combination therapy led to significant improvements in neurological performance, accompanied by downregulation of pyroptosis‐associated proteins and pro‐inflammatory cytokines, as well as enhanced activation of the PINK‐1/Parkin mitophagy pathway and improved antioxidant status. The neuroprotective effects of the combined treatment were abolished by Mdv‐1, indicating a critical role for mitophagy in mediating these benefits. The combination of sinomenine and metformin confers additive neuroprotection against cerebral IR injury in diabetic rats, primarily through inhibition of NLRP3‐mediated pyroptosis and activation of the PINK‐1/Parkin mitophagy pathway. These findings highlight a promising therapeutic strategy for diabetic stroke and warrant further preclinical and clinical investigation.