Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791, Bochum, Germany.
Nat Commun. 2017 Dec 19;8(1):1990. doi: 10.1038/s41467-017-02119-6.
The treatment of progressive multiple sclerosis (MS) is unsatisfactory. One reason is that the drivers of disease, which include iron-mediated neurotoxicity, lymphocyte activity, and oxidative stress, are not simultaneously targeted. Here we present a systematic screen to identify generic, orally available medications that target features of progressive MS. Of 249 medications that cross the blood-brain barrier, 35 prevent iron-mediated neurotoxicity in culture. Of these, several antipsychotics and antidepressants strongly reduce T-cell proliferation and oxidative stress. We focus on the antidepressant clomipramine and found that it additionally inhibits B-lymphocyte activity. In mice with experimental autoimmune encephalomyelitis, a model of MS, clomipramine ameliorates clinical signs of acute and chronic phases. Histologically, clomipramine reduces inflammation and microglial activation, and preserves axonal integrity. In summary, we present a systematic approach to identify generic medications for progressive multiple sclerosis with the potential to advance rapidly into clinical trials, and we highlight clomipramine for further development.
进展性多发性硬化症（MS）的治疗效果不尽人意。原因之一是，疾病的驱动因素包括铁介导的神经毒性、淋巴细胞活性和氧化应激等，并不能同时得到靶向治疗。在这里，我们进行了系统筛选，以确定可用于治疗进展性 MS 的通用、口服药物。在 249 种可穿透血脑屏障的药物中，有 35 种可预防培养中的铁介导神经毒性。其中，一些抗精神病药和抗抑郁药可强烈抑制 T 细胞增殖和氧化应激。我们专注于研究抗抑郁药氯米帕明，发现它还可以抑制 B 淋巴细胞的活性。在实验性自身免疫性脑脊髓炎（MS 的动物模型）小鼠中，氯米帕明可改善急性和慢性期的临床症状。组织学上，氯米帕明可减少炎症和小胶质细胞激活，并保持轴突完整性。综上所述，我们提出了一种系统的方法来鉴定用于进展性多发性硬化症的通用药物，这些药物有可能迅速进入临床试验，我们特别强调氯米帕明具有进一步开发的潜力。
