Pramipexole alleviates ferroptosis in HT22 cells induced by oxygen–glucose deprivation/reoxygenation via the Nrf2/SLC7A11/GPX4 pathway

Pramipexole, a dopamine receptor agonist, is clinically employed in the treatment of Parkinson’s disease. Accumulating evidence has demonstrated that it can enhance neurological function following cerebral ischemia–reperfusion via multiple mechanisms. This study is designed to explore whether pramipexole exerts a protective effect on neurons subjected to oxygen–glucose deprivation/reperfusion by inhibiting the ferroptosis pathway. Firstly, CCK8 assay was employed to evaluate cell viability to determine the optimal intervention time and dosage during oxygen–glucose deprivation/reperfusion injury. Mitochondrial function was evaluated via transmission electron microscopy and JC-1 fluorescent probe. Intracellular iron, glutathione, and glutathione peroxidase 4 enzyme activity were measured using ELISA. Ferroptosis-related proteins and genes were analyzed by immunofluorescence, real-time qPCR, and western blot. And then, a ferroptosis inducer (Erastin) was used as a positive control to validate the link between pramipexole’s effects and ferroptosis regulation. Oxygen–glucose deprivation/reperfusion exposure reduced cell viability, impaired mitochondrial membrane potential, elevated intracellular iron and reactive oxygen species, and suppressed antioxidant capacity. Pramipexole treatment reversed these pathological changes and activated the nuclear factor E2-related factor 2/solute carrier family 7 member 11/glutathione peroxidase 4 signaling axis. Erastin recapitulated oxygen–glucose deprivation/reperfusion-induced cellular dysfunction, which was also mitigated by pramipexole. Pramipexole alleviates oxygen–glucose deprivation/reperfusion-induced neuronal damage and oxidative stress by activating the nuclear factor E2-related factor 2/solute carrier family 7 member 11/glutathione peroxidase 4 pathway to inhibit ferroptosis, highlighting its potential as a therapeutic agent for cerebral ischemia–reperfusion injury.