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Preterm white matter injury (PWMI) is the most common form of brain damage in premature infants caused by hypoxia-ischemia (HI), inflammation, or excitotoxicity. It is characterized by oligodendrocyte precursor cell (OPC) differentiation disorder and dysmyelination. Our previous study confirmed that alpha-asarone (α-asaronol), a major compound isolated from the Chinese medicinal herb Acorus gramineus by our lab, could alleviate neuronal overexcitation and improve the cognitive function of aged rats. In the present study, we investigated the effect and mechanism of α-asaronol on myelination in a rat model of PWMI induced by HI. Notably, α-asaronol promoted OPC differentiation and myelination in the corpus callosum of PWMI rats. Meanwhile, the concentration of glutamate was significantly decreased, and the levels of PPARγ and glutamate transporter 1 (GLT-1) were increased by α-asaronol treatment. In vitro, it was also confirmed that α-asaronol increased GLT-1 expression and recruitment of the PPARγ coactivator PCG-1a in astrocytes under oxygen and glucose deprivation (OGD) conditions. The PPARγ inhibitor GW9662 significantly reversed the effect of α-asaronol on GLT-1 expression and PCG-1a recruitment. Interestingly, the conditioned medium from α-asaronol-treated astrocytes decreased the number of OPCs and increased the number of mature oligodendrocytes. These results suggest that α-asaronol can promote OPC differentiation and relieve dysmyelination by regulating glutamate levels via astrocyte PPARγ-GLT-1 signaling. Although whether α-asaronol binds to PPARγ directly or indirectly is not investigated here, this study still indicates that α-asaronol may be a promising small molecular drug for the treatment of myelin-related diseases.

MicroRNAs are powerful regulators of gene expression in physiological and pathological conditions. We previously showed that the dysregulation of miR-384 resulted in a T helper cell 17 (Th17) imbalance and contributed to the pathogenesis of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. In this study, we evaluated the molecular mechanisms underlying the abnormal increase in miR-384. We did not detect typical CpG islands in the Mir384 promoter. Based on a bioinformatics analysis of the promoter, we identified three conserved transcription factor binding regions (R I , R II , and R III), two of which (R II and R III) were cis-regulatory elements. Furthermore, we showed that signal transducer and activator of transcription 3 (STAT3) bound to specific sites in R II and R III based on chromatin immunoprecipitation, electrophoretic mobility shift assays, and site-specific mutagenesis. During Th17 polarization in vitro, STAT3 activation up-regulated miR-384, while a STAT3 phosphorylation inhibitor decreased miR-384 levels and reduced the percentage of IL-17 + cells, IL-17 secretion, and expression of the Th17 lineage marker Rorγt. Moreover, the simultaneous inhibition of STAT3 and miR-384 could further block Th17 polarization. These results indicate that STAT3, rather than DNA methylation, contributes to the regulation of miR-384 during Th17 polarization.