Melatonin regulates microglial polarization and protects against ischemic stroke-induced brain injury in mice

Ischemic stroke is a leading cause of mortality and morbidity worldwide, with neuroinflammation playing a key role in its pathophysiology. Microglia, the primary immune cells in the brain, undergo rapid activation and phenotypic polarization, which are crucial for regulating neuroinflammatory responses following ischemic stroke. Melatonin is a promising neuroprotective agent that can regulate microglial polarization in central nervous system (CNS) diseases. However, the specific mechanism underlying the neuroprotective effects of melatonin against ischemic stroke-induced brain injury by modulating microglial polarization after ischemic stroke remains poorly understood. To investigate this mechanism, we used the transient middle cerebral artery occlusion/reperfusion (tMCAO/R) model in C57BL/6 mice to induce ischemic stroke and administered intraperitoneal melatonin (20 mg/kg) or an equivalent volume of vehicle daily after reperfusion. Our results demonstrated that melatonin treatment reduced the infarct volume, prevented neuronal loss and apoptosis, and improved neurological deficits after ischemic stroke. Furthermore, melatonin attenuated microglial activation and reactive astrogliosis, while promoting the polarization of microglia toward M2 phenotype via signal transducer and activator of transcription 1/6 (STAT1/6) pathways. Collectively, these findings suggest that melatonin exerts neuroprotective effects against ischemic stroke-induced brain injury by modulating microglial polarization toward M2 phenotype and has the potential as a promising candidate for the treatment of ischemic stroke.