Alpha-asaronol promoted oligodendrocyte precursor cell differentiation and improved myelination as an activator PPAR

Preterm white matter injury (PWMI), characterized by oligodendrocyte precursor cell (OPC) differentiation disorder and dysmyelination, is a prevalent demyelinating disease of the central nervous system in premature infants, necessitating the development of mitigating strategies. Convincing evidence suggests that peroxisome proliferator-activated receptor ? (PPAR?) activation is a stimulative factor against the hindered process of oligodendrocyte (OL) differentiation. However, much remains unknown about its promotive mechanism. Our previous study indicated that alpha-asaronol (a-asaronol) could alleviate myelination disorder in a neonatal PWMI rat model, but the mechanism remained unclear. In this study, we demonstrated that a-asaronol attenuated cognitive deficits, repaired myelin damage, and stimulated OL differentiation in the corpus callosum of PWMI rats. Co-immunoprecipitation analysis confirmed that a-asaronol induced the binding of PPAR? with its coactivator peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1a), which in turn activated oligodendroglial PPAR?. This activation subsequently upregulated the expression of phosphatase and tensin homolog (PTEN) and pro-differentiation-associated genes of Cnp1 and Klk6 and downregulated the expression of Clk1. However, the benefits of a-asaronol were blocked by GW9662, an antagonist of PPAR?. Moreover, a-asaronol also promoted OPC differentiation under oxygen-glucose deprivation conditions. In conclusion, a-asaronol can promote OL differentiation and myelination and alleviate cognitive deficits in neonatal PWMI rats by activating PPAR? and modulating OL differentiation-associated gene expression. This study suggests that a-asaronol may be a potential therapeutic drug for myelination failure in PWMI.