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

IF 8.3 2区材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY

ACS Applied Materials & Interfaces Pub Date : 2024-09-01 DOI:10.1016/j.neurot.2024.e00424

Yanhui Duan , Chenyuan Ye , Jingyi Liao , Xin Xie

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引用次数: 0

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.

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LY2940094 是一种 NOPR 拮抗剂，它能以独立于 NOPR 的方式促进少突胶质细胞的生成和髓鞘的恢复。

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，髓鞘由少突胶质细胞生成，而少突胶质细胞是从少突胶质祖细胞（OPC）分化而来。在脱髓鞘疾病中，OPC 的分化能力受损，髓鞘再形成受到抑制。通过促进OPC分化来促进再髓鞘化是治疗脱髓鞘疾病的一种新策略。阿片系统由四种受体及其配体组成，与 OPC 分化和髓鞘形成有关。然而，每种阿片受体和相关药理分子在OPC分化和髓鞘形成中的确切作用仍不明确。本研究利用每种阿片受体的特异性激动剂和拮抗剂来探讨阿片受体在OPC分化中的功能。研究发现，在体外和体内模型中，Nociceptin/orphanin FQ受体（NOPR）特异性拮抗剂LY2940094都能刺激OPC分化和髓鞘化。出乎意料的是，其他 NOPR 配体并不影响 OPC 的分化，而 NOPR 敲除也不会模拟或阻碍 LY2940094 的作用。研究发现，LY2940094 可调节少突胶质细胞分化相关转录因子 ID4 和 Myrf 的表达，但具体机制仍不清楚。由于 LY2940094 已用于治疗抑郁症和酒精依赖症的临床试验，并显示出可接受的安全性，因此它可能是治疗脱髓鞘疾病的另一种方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Applied Materials & Interfaces 工程技术-材料科学：综合

CiteScore

16.00

自引率

6.30%

发文量

4978

审稿时长

1.8 months

期刊介绍： ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.