Miconazole activates MAPK-driven oligodendrogenesis to promote myelin regeneration and neurological recovery after subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) induces multifaceted brain injuries, with white matter injury (WMI) exhibiting dual pathological features resembling traumatic brain injury and cerebral ischemia. Inflammatory responses triggered by SAH lead to extensive axonal and myelin disintegration in white matter, resulting in severe neurological dysfunction. Myelin regeneration post-injury primarily relies on promoting the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). We observed significant alterations in myelin basic protein (MBP) levels in human SAH brain tissues, paralleled by reduced MBP expression in rat brains post-SAH. SAH rats exhibited marked neurological deficits compared to sham group, alongside disrupted myelin integrity. Dynamic changes in OPC and OL populations were identified post-SAH. Miconazole (MCZ), an antifungal medication approved by Food and Drug Administration (FDA), has previously demonstrated neurorestorative properties. Using the mitogen-activated protein kinase (MAPK) pathway inhibitor GSK1120212, it was observed that the MAPK pathway could be effectively reverted, thereby counteracting the effects induced by MCZ. Our findings reveal that MCZ restores MBP expression, enhances OPC-to-OL differentiation, and accelerates myelin regeneration by activating MAPK signaling pathway. This provides a novel therapeutic strategy for mitigating neurological deficits in SAH patients.