School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Neurotherapeutics. 2024 Sep;21(5):e00424. doi: 10.1016/j.neurot.2024.e00424.
The myelin sheath plays crucial roles in brain development and neuronal functions. In the central nervous system, myelin is generated by oligodendrocytes, that differentiate from oligodendrocyte progenitor cells (OPC). In demyelinating diseases, the differentiation capacity of OPC is impaired and remyelination is dampened. Boosting remyelination by promoting OPC differentiation is a novel strategy for the treatment of demyelinating diseases. The opioid system, which consists of four receptors and their ligands, has been implicated in OPC differentiation and myelin formation. However, the exact roles of each opioid receptor and the relevant pharmacological molecules in OPC differentiation and myelin formation remain elusive. In the present study, specific agonists and antagonists of each opioid receptor were used to explore the function of opioid receptors in OPC differentiation. Nociceptin/orphanin FQ receptor (NOPR) specific antagonist LY2940094 was found to stimulate OPC differentiation and myelination in both in vitro and in vivo models. Unexpectedly, other NOPR ligands did not affect OPC differentiation, and NOPR knockdown did not mimic or impede the effect of LY2940094. LY2940094 was found to modulate the expression of the oligodendrocytes differentiation-associated transcription factors ID4 and Myrf, although the exact mechanism remains unclear. Since LY2940094 has been tested clinically to treat depression and alcohol dependency and has displayed an acceptable safety profile, it may provide an alternative approach to treat demyelinating diseases.
髓鞘在大脑发育和神经元功能中起着至关重要的作用。在中枢神经系统中，少突胶质细胞产生髓鞘，少突胶质细胞由少突胶质前体细胞（OPC）分化而来。在脱髓鞘疾病中，OPC 的分化能力受损，髓鞘再生受到抑制。通过促进 OPC 分化来增强髓鞘再生是治疗脱髓鞘疾病的一种新策略。由四个受体及其配体组成的阿片样物质系统被认为与 OPC 分化和髓鞘形成有关。然而，每个阿片受体以及相关的药理学分子在 OPC 分化和髓鞘形成中的确切作用仍然难以捉摸。在本研究中，使用每个阿片受体的特异性激动剂和拮抗剂来探索阿片受体在 OPC 分化中的功能。发现孤啡肽/N 端前体原（NOPR）特异性拮抗剂 LY2940094 可刺激体外和体内模型中的 OPC 分化和髓鞘形成。出乎意料的是，其他 NOPR 配体不会影响 OPC 分化，并且 NOPR 敲低不会模拟或阻碍 LY2940094 的作用。LY2940094 被发现调节少突胶质细胞分化相关转录因子 ID4 和 Myrf 的表达，尽管确切的机制尚不清楚。由于 LY2940094 已在临床上用于治疗抑郁症和酒精依赖症，并显示出可接受的安全性，因此它可能为治疗脱髓鞘疾病提供一种替代方法。
