Denny Lisa, Al Abadey Afnan, Robichon Katharina, Templeton Nikki, Prisinzano Thomas E, Kivell Bronwyn M, La Flamme Anne C
School of Biological Sciences Victoria University of Wellington Wellington New Zealand.
Centre for Biodiscovery Victoria University of Wellington Wellington New Zealand.
Clin Transl Immunology. 2021 Jan 17;10(1):e1234. doi: 10.1002/cti2.1234. eCollection 2021.
Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to the myelin sheath, resulting in physical and cognitive disability. There is currently no cure for MS, and finding effective treatments to prevent disease progression has been challenging. Recent evidence suggests that activating kappa opioid receptors (KOR) has a beneficial effect on the progression of MS. Although many KOR agonists like U50,488 are not suitable for clinical use because of a poor side-effect profile, nalfurafine is a potent, clinically used KOR agonist with a favorable side-effect profile.
Using the experimental autoimmune encephalomyelitis (EAE) model, the effect of therapeutically administered nalfurafine or U50,488 on remyelination, CNS infiltration and peripheral immune responses were compared. Additionally, the cuprizone model was used to compare the effects on non-immune demyelination.
Nalfurafine enabled recovery and remyelination during EAE. Additionally, it was more effective than U50,488 and promoted disease reduction when administered after chronic demyelination. Blocking KOR with the antagonist, nor-BNI, impaired full recovery by nalfurafine, indicating that nalfurafine mediates recovery from EAE in a KOR-dependent fashion. Furthermore, nalfurafine treatment reduced CNS infiltration (especially CD4 and CD8 T cells) and promoted a more immunoregulatory environment by decreasing Th17 responses. Finally, nalfurafine was able to promote remyelination in the cuprizone demyelination model, supporting the direct effect on remyelination in the absence of peripheral immune cell invasion.
Overall, our findings support the potential of nalfurafine to promote recovery and remyelination and highlight its promise for clinical use in MS.
多发性硬化症（MS）是一种神经退行性疾病，其特征为炎症和髓鞘损伤，导致身体和认知功能障碍。目前尚无治愈MS的方法，寻找有效的治疗方法以预防疾病进展一直具有挑战性。最近的证据表明，激活κ阿片受体（KOR）对MS的进展具有有益作用。尽管许多KOR激动剂，如U50,488，由于副作用较大而不适合临床使用，但纳曲酮是一种有效的、临床使用的KOR激动剂，具有良好的副作用特征。
使用实验性自身免疫性脑脊髓炎（EAE）模型，比较治疗性给予纳曲酮或U50,488对再髓鞘化、中枢神经系统浸润和外周免疫反应的影响。此外，使用铜螯合剂模型比较对非免疫性脱髓鞘的影响。
纳曲酮在EAE期间能够促进恢复和再髓鞘化。此外，它比U50,488更有效，并且在慢性脱髓鞘后给予时能促进疾病减轻。用拮抗剂nor-BNI阻断KOR会损害纳曲酮的完全恢复，表明纳曲酮以KOR依赖的方式介导从EAE的恢复。此外，纳曲酮治疗减少了中枢神经系统浸润（特别是CD4和CD8 T细胞），并通过降低Th17反应促进了更具免疫调节性的环境。最后，纳曲酮能够在铜螯合剂脱髓鞘模型中促进再髓鞘化，支持在没有外周免疫细胞入侵的情况下对再髓鞘化的直接作用。
总体而言，我们的研究结果支持纳曲酮促进恢复和再髓鞘化的潜力，并突出了其在MS临床应用中的前景。
