Matrine attenuates cerebral ischemia-reperfusion injury via UCP2/AMPKα-mediated suppression of oxidative stress, apoptosis, and neuroinflammation.

Ischemic stroke remains a major contributor to disability and mortality, emphasizing the urgent need for new therapies to enhance reperfusion treatment outcomes. In this study, we systematically investigated the neuroprotective effects of matrine, an alkaloid derived from Sophora flavescens, using both computational and experimental approaches. Initially, a network pharmacology strategy was employed to identify 69 potential targets of matrine relevant to ischemic stroke by integrating data from Swiss Target Prediction, Similarity Ensemble Approach, PharmMapper, and GeneCards. Subsequent protein-protein interaction analyses, along with GO and KEGG pathway enrichment, highlighted the AMPK signaling pathway as a critical mediator. To validate these findings, male C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAO) to induce stroke. Matrine treatment in this model resulted in significant improvements in neurological function, reductions in brain damage, and marked decreases in oxidative stress and apoptosis. Furthermore, molecular docking and molecular dynamics (MD) simulations studies revealed a strong binding affinity between matrine and key targets such as AMPK, CHRNA4, and SLC6A3, with Western blot analyses confirming the involvement of AMPK and its upstream regulator UCP2. Collectively, our results demonstrate that matrine confers neuroprotection in cerebral ischemia-reperfusion injury by modulating the AMPK pathway, suggesting its potential as a novel therapeutic agent for ischemic stroke. The proposed mechanisms of matrine in ischemic stroke are summarized in the graphical abstract.