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<p>Epilepsy is a common neurological disorder often accompanied by hippocampal myelin damage and impaired differentiation of oligodendrocyte precursor cells (OPCs). This study aimed to investigate the regulatory effects of Saracatinib on myelin regeneration and OPC maturation in a mouse model of epilepsy, as well as its underlying mechanisms, to provide new strategies for the treatment of epilepsy-related myelin damage. Changes in hippocampal myelin structure were observed using Fast Blue staining and transmission electron microscopy. Immunofluorescence was used to detect the number of oligodendrocyte precursor cell (OPCs, PDGFRα) and mature oligodendrocytes (ODCs, MBP+). Cell culture experiments verified the effects of Saracatinib on OPC differentiation, and SwissTargetPrediction and GSEA were used to predict its targets. Western blot and immunofluorescence further validated the role of the NOTCH1 signaling pathway in Saracatinib-mediated OPC differentiation. Saracatinib Reduced the Racine Score, Prolonged Seizure Latency, and Decreased Seizure Duration in an Epileptic Mouse Model. Epileptic model mice exhibited significant hippocampal myelin damage, characterized by thinning of myelin sheaths, reduced myelin quantity, and increased axonal exposure. Saracatinib treatment significantly improved myelin structure, restored myelin thickness and continuity, and alleviated axonal atrophy. Immunofluorescence showed that Saracatinib increased MBP expression and decreased PDGFRα expression, promoting the differentiation of OPCs into ODCs. Bioinformatics analysis and experimental validation demonstrated that Saracatinib promoted OPC maturation by inhibiting the NOTCH1 signaling pathway, and this effect could be reversed by the NOTCH1 agonist JAG1. Saracatinib significantly promotes hippocampal myelin regeneration and OPC maturation in epileptic mice by inhibiting the NOTCH1 signaling pathway, providing a potential molecular target and therapeutic strategy for the treatment of epilepsy-related myelin damage.</p>

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Saracatinib Promotes Hippocampal Myelin Regeneration and Oligodendrocyte Precursor Cell Maturation by Inhibiting the NOTCH1 Signaling Pathway in Epileptic Mice

  • 期刊论文

  • 发表日期：

    2025年12月9日

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  • Xinming Luo,
  • Wenyue Wu,
  • Baiqi Yu,
  • Sisi Chen,
  • Jing Zhao,
  • Jun Min,
  • Xunhu Gu

摘要

Epilepsy is a common neurological disorder often accompanied by hippocampal myelin damage and impaired differentiation of oligodendrocyte precursor cells (OPCs). This study aimed to investigate the regulatory effects of Saracatinib on myelin regeneration and OPC maturation in a mouse model of epilepsy, as well as its underlying mechanisms, to provide new strategies for the treatment of epilepsy-related myelin damage. Changes in hippocampal myelin structure were observed using Fast Blue staining and transmission electron microscopy. Immunofluorescence was used to detect the number of oligodendrocyte precursor cell (OPCs, PDGFRα) and mature oligodendrocytes (ODCs, MBP+). Cell culture experiments verified the effects of Saracatinib on OPC differentiation, and SwissTargetPrediction and GSEA were used to predict its targets. Western blot and immunofluorescence further validated the role of the NOTCH1 signaling pathway in Saracatinib-mediated OPC differentiation. Saracatinib Reduced the Racine Score, Prolonged Seizure Latency, and Decreased Seizure Duration in an Epileptic Mouse Model. Epileptic model mice exhibited significant hippocampal myelin damage, characterized by thinning of myelin sheaths, reduced myelin quantity, and increased axonal exposure. Saracatinib treatment significantly improved myelin structure, restored myelin thickness and continuity, and alleviated axonal atrophy. Immunofluorescence showed that Saracatinib increased MBP expression and decreased PDGFRα expression, promoting the differentiation of OPCs into ODCs. Bioinformatics analysis and experimental validation demonstrated that Saracatinib promoted OPC maturation by inhibiting the NOTCH1 signaling pathway, and this effect could be reversed by the NOTCH1 agonist JAG1. Saracatinib significantly promotes hippocampal myelin regeneration and OPC maturation in epileptic mice by inhibiting the NOTCH1 signaling pathway, providing a potential molecular target and therapeutic strategy for the treatment of epilepsy-related myelin damage.