Melatonin promotes recovery from ischemic stroke by modulating microglia polarization and inhibiting oligodendrocyte pyroptosis via the RORα/AMPKα/STAT1 pathway

This study investigates how melatonin affects white matter damage and oligodendrocyte pyroptosis after ischemic stroke by modulating microglia polarization through the RORα/AMPKα/STAT1 pathway. A mouse model of middle cerebral artery occlusion (MCAO) was used, with melatonin (20 mg/kg) administered post-reperfusion and daily for 14 days. Neurological function and white matter damage were assessed, along with gasdermin D (GSDMD) and caspase-1 expression to evaluate pyroptosis. In vitro, a Transwell co-culture system of microglia and oligodendrocytes exposed to oxygen-glucose deprivation (OGD) was employed. The role of RORα in modulating microglia polarization and oligodendrocyte pyroptosis was explored using siRNA-mediated knockdown and AAV-based RORα shRNA microinjection. Melatonin reduced white matter injury, inhibited oligodendrocyte pyroptosis, and improved sensorimotor function. These effects were linked to reduced APC/caspase-1 and APC/GSDMD double-positive cells and were dependent on RORα signaling. Melatonin also shifted microglia from a pro-inflammatory to an anti-inflammatory phenotype, an effect reversed by RORα knockdown. In vitro, melatonin inhibited OGD-induced pyroptosis via the RORα/AMPKα/STAT1 pathway. These findings suggest that melatonin promotes long-term recovery by reducing neuroinflammation and protecting white matter integrity through RORα signaling, highlighting its potential as a therapeutic agent for stroke recovery.