The protection of 2-D08 to sevoflurane-induced hypomyelination is mediated by Kir4.1

Background and Purpose: The developing brain of infants and young children is in a critical period of myelination, where prolonged or repeated general anesthesia can lead to hypomyelination. However, there is currently no effective treatment, highlighting the urgent need for new therapeutic strategies. Kir4.1 plays pivotal roles in the process of myelination, besides, 2-D08 up-regulates the expression of the Kir4.1 in oligodendrocyte precursor cells (OPCs). Whether 2-D08 could prevent long-term hypomyelination of anesthesia remains to be elucidated. Experimental Approach: We used plasmid vector construction, behavioral experiments, immunohistochemistry, ELISA, and OPCs culture to investigate the effects of 2-D08 on myelin development in sevoflurane-exposed rat. Key Results: We found that administration of 2-D08 in sevoflurane-exposed rat markedly attenuated OPCs antigen presentation and IL-6/IL-1β secretion, and ameliorated OPCs differentiation deficits, ultimately restoring motor function of rat. Instead, these improvements in OPCs differentiation were dissipated in Kir4.1 cKO condition in the presence of 2-D08 after sevoflurane. Conclusions and Implications: The effects of 2-D08 primarily stem from the activation of Kir4.1 channels. We provided a novel theoretical basis and effective intervention strategies for the clinical treatment of diseases with anesthesia-induced hypomyelination.