2. Academic Validation
  3. LY2940094, an NOPR antagonist, promotes oligodendrocyte generation and myelin recovery in an NOPR independent manner

LY2940094, an NOPR antagonist, promotes oligodendrocyte generation and myelin recovery in an NOPR independent manner

  • Neurotherapeutics. 2024 Jul 13:e00424. doi: 10.1016/j.neurot.2024.e00424.
Yanhui Duan 1,  Chenyuan Ye 2,  Jingyi Liao 2,  Xin Xie 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 2 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.
  • 3 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; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, China. Electronic address: xxie@simm.ac.cn.
PMID: 39004556 DOI: 10.1016/j.neurot.2024.e00424
Abstract

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.

Keywords

LY2940094; Myelin sheath; Nociceptin/orphanin FQ receptor; Oligodendrocyte; Oligodendrocyte progenitor cell; Remyelination.

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