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

  • Biomed Pharmacother. 2023 May 3;163:114815. doi: 10.1016/j.biopha.2023.114815.
Zhaowei Feng  1 ,  Zixuan Gao  2 ,  Renyu Kong  2 ,  Tao Zhuang  2 ,  Jing Liu  2 ,  Ting Liu  3 ,  Xiaohui Zheng  4 ,  Yajun Bai  5 ,  Ruiqin Yao  6
Affiliations
  • 1. Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China; Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
  • 2. Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
  • 3. Nursing Department, Xuzhou Pharmaceutical Branch of Jiangsu Union Technical Institute, Xuzhou, Jiangsu Province, China.
  • 4. Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, China.
  • 5. Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, China. Electronic address: [email protected].
  • 6. Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: [email protected].
PMID: 37146420 DOI: 10.1016/j.biopha.2023.114815
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.

Keywords
Differentiation; PPARγ; White matter injury; alpha-asaronol; oligodendrocyte precursor cell.
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