Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, 11 rue Humann, 67 000 Strasbourg, France.
Laboratoire d'innovation thérapeutique (LIT) CNRS UMR 7200, Faculté de Pharmacie de Strasbourg, 74 route du Rhin, CS 60024, 67401 Illkirch Cedex, France.
Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3016-3027. doi: 10.1016/j.bbadis.2017.09.007. Epub 2017 Sep 9.
Multiple sclerosis (MS) is a severe autoimmune disease characterized by inflammatory, demyelinating and neurodegenerative components causing motor, sensory, visual and/or cognitive symptoms. The relapsing-remitting MS affecting 85% of patients is reliably mimicked by the proteolipid-protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) SJL/J-mouse model. Significant progress was made for MS treatment but the development of effective therapies devoid of severe side-effects remains a great challenge. Here, we combine clinical, behavioral, histopathological, biochemical and molecular approaches to demonstrate that low and well tolerated doses (10-20mg/kg) of TSPO ligand XBD173 (Emapunil) efficiently ameliorate clinical signs and neuropathology of PLP-EAE mice. In addition to the conventional clinical scoring of symptoms, we applied the robust behavioral Catwalk-method to confirm that XBD173 (10mg/kg) increases the maximum contact area parameter at EAE-disease peak, indicating an improvement/recovery of motor functions. Consistently, histopathological studies coupled with microscope-cellSens quantification and RT-qPCR analyzes showed that XBD173 prevented demyelination by restoring normal protein and mRNA levels of myelin basic protein that was significantly repressed in PLP-EAE mice spinal cord and brain. Interestingly, ELISA-based measurement revealed that XBD173 increased allopregnanolone concentrations in PLP-EAE mice spinal and brain tissues. Furthermore, flow cytometry assessment demonstrated that XBD173 therapy decreased serum level of pro-inflammatory cytokines, including interleukin-17A, Interleukin-6 and tumor-necrosis-factor alpha in PLP-EAE mice. As the optimal XBD173 dosing exerting the maximal beneficial action in EAE mice is the lower 10mg/kg dose, the paper opens interesting perspectives for the development of efficient and safe therapies against MS with slight or no side-effects.
多发性硬化症（MS）是一种严重的自身免疫性疾病，其特征为炎症、脱髓鞘和神经退行性病变，导致运动、感觉、视觉和/或认知症状。影响 85%患者的复发缓解型多发性硬化症可通过蛋白脂质蛋白（PLP）诱导的实验性自身免疫性脑脊髓炎（EAE）SJL/J 小鼠模型可靠地模拟。尽管多发性硬化症的治疗取得了显著进展，但开发无严重副作用的有效疗法仍然是一个巨大的挑战。在这里，我们结合临床、行为、组织病理学、生物化学和分子方法，证明低剂量（10-20mg/kg）和良好耐受的 TSPO 配体 XBD173（Emapunil）能够有效改善 PLP-EAE 小鼠的临床症状和神经病理学。除了传统的临床症状评分外，我们还应用稳健的行为 Catwalk 方法来确认 XBD173（10mg/kg）在 EAE 疾病高峰期增加最大接触面积参数，表明运动功能的改善/恢复。一致地，组织病理学研究结合显微镜细胞 Sens 定量和 RT-qPCR 分析表明，XBD173 通过恢复髓鞘碱性蛋白的正常蛋白和 mRNA 水平来防止脱髓鞘，而髓鞘碱性蛋白在 PLP-EAE 小鼠脊髓和大脑中显著受到抑制。有趣的是，ELISA 测量显示 XBD173 增加了 PLP-EAE 小鼠脊髓和脑组织中的别孕烯醇酮浓度。此外，流式细胞术评估表明，XBD173 治疗降低了 PLP-EAE 小鼠血清中促炎细胞因子（包括白细胞介素-17A、白细胞介素-6 和肿瘤坏死因子-α）的水平。由于在 EAE 小鼠中发挥最大有益作用的最佳 XBD173 剂量是较低的 10mg/kg 剂量，因此该论文为开发针对多发性硬化症的高效、安全的治疗方法提供了有趣的前景，这些方法具有轻微或无副作用。
