Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment CRBS de la Faculté de Médecine, 1 rue Eugène Boeckel, 67 000, Strasbourg, France.
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy.
Mol Neurobiol. 2022 Mar;59(3):1744-1765. doi: 10.1007/s12035-022-02737-2. Epub 2022 Jan 11.
Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system (CNS) caused by CNS infiltration of peripheral immune cells, immune-mediated attack of the myelin sheath, neuroinflammation, and/or axonal/neuronal dysfunctions. Some drugs are available to cope with relapsing-remitting MS (RRMS) but there is no therapy for the primary progressive MS (PPMS). Because growing evidence supports a regulatory role of the translocator protein (TSPO) in neuroinflammatory, demyelinating, and neurodegenerative processes, we investigated the therapeutic potential of phenylindolyilglyoxylamydes (PIGAs) TSPO ligands in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mice mimicking the human PPMS. MOG-EAE C57Bl/6-mice were treated by TSPO ligands PIGA839, PIGA1138, or the vehicle. Several methods were combined to evaluate PIGAs-TSPO ligand effects on MOG-EAE symptoms, CNS infiltration by immune cells, demyelination, and axonal damages. PIGA1138 (15 mg/kg) drastically reduced MOG-EAE mice clinical scores, ameliorated motor dysfunctions assessed with the Catwalk device, and counteracted MOG-EAE-induced demyelination by preserving Myelin basic protein (MBP) expression in the CNS. Furthermore, PIGA1138-treatment prevented EAE-evoked decreased neurofilament-200 expression in spinal and cerebellar axons. Moreover, PIGA1138 inhibited peripheral immune-CD45 + cell infiltration in the CNS, suggesting that it may control inflammatory mechanisms involved in PPMS. Concordantly, PIGA1138 enhanced anti-inflammatory interleukin-10 serum level in MOG-EAE mice. PIGA1138-treatment, which increased neurosteroid allopregnanolone production, ameliorated all pathological biomarkers, while PIGA839, unable to activate neurosteroidogenesis in vivo, exerted only moderate/partial effects in MOG-EAE mice. Altogether, our results suggest that PIGA1138-based treatment may represent an interesting possibility to be explored for the innovation of effective therapies against PPMS.
多发性硬化症（MS）是一种中枢神经系统（CNS）的自身免疫性和脱髓鞘疾病，由外周免疫细胞浸润中枢神经系统、髓鞘的免疫介导攻击、神经炎症和/或轴突/神经元功能障碍引起。有一些药物可用于应对复发缓解型多发性硬化症（RRMS），但对于原发性进展型多发性硬化症（PPMS）尚无治疗方法。由于越来越多的证据支持转位蛋白（TSPO）在神经炎症、脱髓鞘和神经退行性过程中的调节作用，我们研究了苯基吲哚基乙二酰亚胺（PIGA）TSPO 配体在髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎（EAE）小鼠中的治疗潜力，这些小鼠模拟了人类的 PPMS。MOG-EAE C57Bl/6 小鼠用 TSPO 配体 PIGA839、PIGA1138 或载体治疗。结合使用多种方法来评估 PIGAs-TSPO 配体对 MOG-EAE 症状、免疫细胞浸润中枢神经系统、脱髓鞘和轴突损伤的影响。PIGA1138（15mg/kg）显著降低了 MOG-EAE 小鼠的临床评分，改善了 Catwalk 设备评估的运动功能障碍，并通过保留中枢神经系统中的髓鞘碱性蛋白（MBP）表达来对抗 MOG-EAE 诱导的脱髓鞘。此外，PIGA1138 治疗可防止 EAE 引起的脊髓和小脑轴突中神经丝-200 表达降低。此外，PIGA1138 抑制了中枢神经系统中外周免疫-CD45+细胞的浸润，这表明它可能控制参与 PPMS 的炎症机制。一致地，PIGA1138 增加了 MOG-EAE 小鼠血清中抗炎性白细胞介素-10 的水平。PIGA1138 治疗增加了神经甾体类物质孕烯醇酮的产生，改善了所有病理生物标志物，而 PIGA839 体内不能激活神经甾体生成，仅在 MOG-EAE 小鼠中发挥中等/部分作用。总之，我们的研究结果表明，基于 PIGA1138 的治疗可能是一种有前途的创新治疗方法，可用于治疗 PPMS。
