Therapeutic Potential of Edaravone for Neuroprotection Following Global Cerebral Hypoxia

Global cerebral hypoxia triggers (mal-)adaptive responses that can lead to neuronal damage. This study evaluated edaravone's neuroprotective effects in a rat hypoxia model, focusing on sex differences, treatment durations, and behavioral outcomes. Male and female rats underwent global cerebral hypoxia induced by rocuronium, with post-hypoxia edaravone treatment. Motor coordination and activity were assessed through exploratory behavior tests. Histological analyses evaluated neuronal integrity and apoptosis, while microglial activity and gene expression were analyzed via immunofluorescence and qPCR. Edaravone showed transient neuroprotective effects on motor behavior and early immune responses, particularly in the cerebellum and hippocampus. No gross morphological damage was observed, though functional impairments occurred despite preserved cytoarchitecture. Microglial activity was initially suppressed in treated and later activated in untreated hypoxic brains, suggesting modulating immune responses. Gene expression analysis revealed region-specific, time-dependent, and sex-specific changes, including early upregulation of CCR7, S100B, and NSE in treated animals. Males were more susceptible to hypoxic damage, while females showed higher baseline resistance and better functional recovery. Seven-day edaravone treatment increased apoptotic markers in male cerebellum, indicating sex-specific differences in cell death mechanisms. These findings highlight the potential for personalized therapy and underscore the importance of considering sex differences in both research and clinical practice.