Abstract：
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 γ (PPARγ) 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 (α-asaronol) could alleviate myelination disorder in a neonatal PWMI rat model, but the mechanism remained unclear. In this study, we demonstrated that α-asaronol attenuated cognitive deficits, repaired myelin damage, and stimulated OL differentiation in the corpus callosum of PWMI rats. Co-immunoprecipitation analysis confirmed that α-asaronol induced the binding of PPARγ with its coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which in turn activated oligodendroglial PPARγ. 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 α-asaronol were blocked by GW9662, an antagonist of PPARγ. Moreover, α-asaronol also promoted OPC differentiation under oxygen-glucose deprivation conditions. In conclusion, α-asaronol can promote OL differentiation and myelination and alleviate cognitive deficits in neonatal PWMI rats by activating PPARγ and modulating OL differentiation-associated gene expression. This study suggests that α-asaronol may be a potential therapeutic drug for myelination failure in PWMI.
摘要：
早产白质损伤（PWMI），以少突胶质细胞前体细胞（OPC）分化障碍和髓鞘障碍为特征，是早产儿中枢神经系统常见的脱髓鞘疾病，有必要制定缓解策略。令人信服的证据表明，过氧化物酶体增殖物激活受体γ（PPARγ）激活是针对少突胶质细胞（OL）分化受阻过程的刺激因子。然而,它的促进机制还不清楚。我们先前的研究表明，α-细辛醇（α-细辛醇）可以缓解新生PWMI大鼠模型中的髓鞘形成障碍，但机制尚不清楚。在这项研究中,我们证明了α-细辛醇减轻了认知缺陷，修复髓鞘损伤，并刺激PWMI大鼠call体的OL分化。免疫共沉淀分析证实，α-细辛醇诱导PPARγ与其共激活剂过氧化物酶体增殖物激活受体γ共激活剂-1α（PGC-1α）的结合，进而激活少突胶质PPARγ。这种激活随后上调了Cnp1和Klk6的磷酸酶和张力蛋白同源物（PTEN）和促分化相关基因的表达，并下调了Clk1的表达。然而,α-细辛醇的益处被PPARγ拮抗剂GW9662阻断。此外，在氧-葡萄糖剥夺条件下,α-细辛醇也促进OPC分化。总之,α-asaronol可通过激活PPARγ和调节OL分化相关基因的表达，促进OL分化和髓鞘形成，减轻新生PWMI大鼠的认知障碍。这项研究表明，α-asaronol可能是PWMI中髓鞘形成失败的潜在治疗药物。
