Dexmedetomidine Improves Long-term Neurological Outcomes by Promoting Oligodendrocyte Genesis and Myelination in Neonatal Rats Following Hypoxic-ischemic Brain Injury.

Neonatal hypoxic-ischemic brain injury (HIBI) can lead to white matter damage, which significantly contributes to cognitive dysfunction, emotional disorders, and sensorimotor impairments. Although dexmedetomidine enhances neurobehavioral outcomes, its impact on oligodendrocyte genesis and myelination following hypoxic-ischemic events, as well as the underlying mechanisms, remain poorly understood. Dexmedetomidine was administered 15 min post-HIBI. We assessed neurobehavioral deficits using various tests: surface righting, negative geotaxis, forelimb grip strength, cliff avoidance, sensory reflexes, novel object recognition, T-maze, and three-chamber social interaction. We also investigated the relationship between myelination and neurobehavioral outcomes. Measurements included oligodendrocyte precursor cell (OPC) proliferation and survival 24 h post-injury, early myelination, and oligodendrocyte differentiation by postnatal day 14. Furthermore, we evaluated microglial activation towards the M2 phenotype and the extent of neuroinflammation during the acute phase. Dexmedetomidine significantly ameliorated long-term neurological deficits caused by HIBI. Pearson linear regression analysis revealed a strong correlation between long-term neurological outcomes and myelin maturity. The treatment notably mitigated the long-term deterioration of myelin formation and maturation following HIBI. This protective effect was primarily due to enhanced OPC proliferation and survival post-HIBI during the acute phase and, to a lesser extent, to the modulation of microglial activity towards the M2 phenotype and a reduction in neuroinflammation. Dexmedetomidine offers substantial protection against long-term neurobehavioral disabilities induced by HIBI, primarily by revitalizing the impaired survival and maturation of oligodendrocyte progenitor cells and promoting myelination.