Department of Neurology, Medical Faculty of the Heinrich-Heine University, Düsseldorf, Germany.
Department of Neurology, Maria Hilf Clinics, Mönchengladbach, Germany.
Front Immunol. 2023 Aug 9;14:1234984. doi: 10.3389/fimmu.2023.1234984. eCollection 2023.
In multiple sclerosis (MS), chronic disability primarily stems from axonal and neuronal degeneration, a condition resistant to conventional immunosuppressive or immunomodulatory treatments. Recent research has indicated that selective sphingosine-1-phosphate receptor S1PR-1 and -5 modulators yield positive effects in progressive MS and mechanistic models of inflammation-driven neurodegeneration and demyelination.
In this study, the S1PR-1/-5 modulator RP-101074 was evaluated as a surrogate for ozanimod in the non-inflammatory, primary degenerative animal model of light-induced photoreceptor loss (LI-PRL) in CX3CR1-GFP mice to assess potential neuroprotective effects, independent of its immunomodulatory mechanism of action.
Prophylactic administration of RP-101074 demonstrated protective effects in the preclinical, non-inflammatory LI-PRL animal model, following a bell-shaped dose-response curve. RP-101074 treatment also revealed activity-modulating effects on myeloid cells, specifically, CX3CR1+ cells, significantly reducing the marked infiltration occurring one week post-irradiation. Treatment with RP-101074 produced beneficial outcomes on both retinal layer thickness and visual function as evidenced by optical coherence tomography (OCT) and optomotor response (OMR) measurements, respectively. Additionally, the myelination status and the quantity of neural stem cells in the optic nerve suggest that RP-101074 may play a role in the activation and/or recruitment of neural stem cells and oligodendrocyte progenitor cells, respectively.
CONCLUSION/DISCUSSION: The data from our study suggest that RP-101074 may have a broader role in MS treatment beyond immunomodulation, potentially offering a novel approach to mitigate neurodegeneration, a core contributor to chronic disability in MS.
在多发性硬化症（MS）中，慢性残疾主要源于轴突和神经元退化，这种情况对传统的免疫抑制或免疫调节治疗有抗性。最近的研究表明，选择性鞘氨醇-1-磷酸受体 S1PR-1 和 -5 调节剂在进行性 MS 和炎症驱动的神经退行性变和脱髓鞘的机制模型中具有积极作用。
在这项研究中，S1PR-1/-5 调节剂 RP-101074 在 CX3CR1-GFP 小鼠的光诱导光感受器丧失（LI-PRL）非炎症性原发性退行性动物模型中被评估为奥扎那肽的替代物，以评估其潜在的神经保护作用，而不考虑其免疫调节作用机制。
预防性给予 RP-101074 在具有钟形剂量反应曲线的临床前非炎症性 LI-PRL 动物模型中显示出保护作用。RP-101074 治疗还显示出对髓样细胞（特别是 CX3CR1+细胞）的活性调节作用，显著减少了照射后一周发生的明显浸润。RP-101074 治疗对视网膜层厚度和视觉功能均产生有益效果，这分别通过光学相干断层扫描（OCT）和光动反应（OMR）测量得到证实。此外，视神经中的髓鞘状态和神经干细胞数量表明，RP-101074 可能在神经干细胞和少突胶质前体细胞的激活和/或募集中发挥作用。
结论/讨论：我们的研究数据表明，RP-101074 在 MS 治疗中的作用可能不仅仅局限于免疫调节，它可能为减轻神经退行性变提供一种新的方法，而神经退行性变是 MS 慢性残疾的核心贡献因素。
