Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium.
Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands.
FASEB J. 2024 Jan 31;38(2):e23413. doi: 10.1096/fj.202301557RR.
Sphingosine-1-phosphate receptor (S1PR) modulators are clinically used to treat relapse-remitting multiple sclerosis (MS) and the early phase of progressive MS when inflammation still prevails. In the periphery, S1PR modulators prevent lymphocyte egress from lymph nodes, hence hampering neuroinflammation. Recent findings suggest a role for S1PR modulation in remyelination. As the Giα-coupled S1P1 subtype is the most prominently expressed S1PR in oligodendrocyte precursor cells (OPCs), selective modulation (functional antagonism) of S1P1 may have direct effects on OPC functionality. We hypothesized that functional antagonism of S1P1 by ponesimod induces remyelination by boosting OPC differentiation. In the cuprizone mouse model of demyelination, we found ponesimod to decrease the latency time of visual evoked potentials compared to vehicle conditions, which is indicative of functional remyelination. In addition, the Y maze spontaneous alternations test revealed that ponesimod reversed cuprizone-induced working memory deficits. Myelin basic protein (MBP) immunohistochemistry and transmission electron microscopy of the corpus callosum revealed an increase in myelination upon ponesimod treatment. Moreover, treatment with ponesimod alone or in combination with A971432, an S1P5 monoselective modulator, significantly increased primary mouse OPC differentiation based on O4 immunocytochemistry. In conclusion, S1P1 functional antagonism by ponesimod increases remyelination in the cuprizone model of demyelination and significantly increases OPC differentiation in vitro.
鞘氨醇-1-磷酸受体（S1PR）调节剂临床上用于治疗复发缓解型多发性硬化症（MS）和炎症仍占主导地位的进展型 MS 的早期阶段。在外周，S1PR 调节剂可防止淋巴细胞从淋巴结中逸出，从而阻碍神经炎症。最近的研究结果表明 S1PR 调节在髓鞘再生中发挥作用。由于 Giα 偶联的 S1P1 亚型是少突胶质前体细胞（OPC）中表达最显著的 S1PR，因此选择性调节（功能拮抗）S1P1 可能对 OPC 功能具有直接影响。我们假设 ponesimod 通过功能性拮抗 S1P1 来增强 OPC 分化，从而诱导髓鞘再生。在脱髓鞘的 Cuprizone 小鼠模型中，我们发现与载体条件相比，ponesimod 可降低视觉诱发电位的潜伏期，这表明具有功能上的髓鞘再生。此外，Y 迷宫自发交替测试表明 ponesimod 逆转了 Cuprizone 诱导的工作记忆缺陷。胼胝体的髓鞘碱性蛋白（MBP）免疫组织化学和透射电镜检查显示，ponesimod 治疗后髓鞘形成增加。此外，ponesimod 单独或与 S1P5 单选择性调节剂 A971432 联合治疗，基于 O4 免疫细胞化学，显著增加了原代小鼠 OPC 的分化。总之，ponesimod 通过功能性拮抗 S1P1 增加了脱髓鞘 Cuprizone 模型中的髓鞘再生，并显著增加了体外 OPC 的分化。
