Abstract

This study investigated the neuroprotective effects and mechanisms of poliumoside (POL) against ischemic stroke, focusing on oxidative stress and mitochondrial dysfunction. Using an Oxygen-Glucose Deprivation/Reperfusion (OGD/R) model in Neuro-2a cells and a photothrombotic stroke model in C57BL/6J mice, we demonstrated that POL treatment significantly improved post-injury outcomes. In mice, POL enhanced motor coordination and grip strength, reduced cerebral infarct volume, and alleviated neuronal damage and apoptosis. Crucially, it suppressed brain oxidative stress, as shown by decreased reactive oxygen species (ROS) levels. In OGD/R-injured Neuro-2a cells, POL dose-dependently increased cell viability, reduced ROS and apoptosis, and improved mitochondrial function by stabilizing membrane potential and attenuating calcium overload. Mechanistically, POL activated the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway antioxidant pathway, promoting Nrf2 nuclear translocation and upregulating downstream proteins Heme oxygenase 1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). It also modulated autophagy by affecting Microtubule-associated proteins 1A/1B light chain 3B (LC3B) and Sequestosome 1 (SQSTM1), and exerted anti-apoptotic effects by regulating B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax). In conclusion, POL confers protection against ischemic injury primarily by mitigating oxidative stress and preserving mitochondrial integrity via activation of the Nrf2 pathway and regulation of associated cellular processes.