Department of Neurology, Ohio State University Medical Center, Columbus, OH 43210, USA.
Ann Neurol. 2010 Apr;67(4):498-507. doi: 10.1002/ana.21935.
To determine if suppressing Nogo-A, an axonal inhibitory protein, will promote functional recovery in a murine model of multiple sclerosis (MS).
A small interfering RNA was developed to specifically suppress Nogo-A (siRNA-NogoA). The siRNA-NogoA silencing effect was evaluated in vitro and in vivo via immunohistochemistry. The siRNA was administered intravenously in 2 models of experimental autoimmune encephalomyelitis (EAE). Axonal repair was measured by upregulation of GAP43. Enzyme-linked immunosorbent assay, flow cytometry, and (3)H-thymidine incorporation were used to determine immunological changes in myelin-specific T cells in mice with EAE.
The siRNA-NogoA suppressed Nogo-A expression in vitro and in vivo. Systemic administration of siRNA-NogoA ameliorated EAE and promoted axonal repair, as demonstrated by enhanced GAP43+ axons in the lesions. Myelin-specific T-cell proliferation and cytokine production were unchanged in the siRNA-NogoA-treated mice.
Silencing Nogo-A in EAE promotes functional recovery. The therapeutic benefit appears to be mediated by axonal growth and repair, and is not attributable to changes in the encephalitogenic capacity of the myelin-specific T cells. Silencing Nogo-A may be a therapeutic option for MS patients to prevent permanent functional deficits caused by immune-mediated axonal damage.
确定抑制轴突抑制蛋白 Nogo-A 是否会促进多发性硬化症（MS）小鼠模型中的功能恢复。
开发了一种小干扰 RNA 来特异性抑制 Nogo-A（siRNA-NogoA）。通过免疫组织化学在体外和体内评估 siRNA-NogoA 的沉默效果。该 siRNA 通过静脉内给药在 2 种实验性自身免疫性脑脊髓炎（EAE）模型中进行了给药。通过 GAP43 的上调来测量轴突修复。酶联免疫吸附试验、流式细胞术和（3）H-胸腺嘧啶掺入用于测定 EAE 小鼠中髓鞘特异性 T 细胞的免疫变化。
siRNA-NogoA 在体外和体内均抑制 Nogo-A 表达。siRNA-NogoA 的全身给药改善了 EAE 并促进了轴突修复，这表现为病变中增强的 GAP43+轴突。siRNA-NogoA 处理的小鼠中，髓鞘特异性 T 细胞的增殖和细胞因子产生没有变化。
在 EAE 中沉默 Nogo-A 可促进功能恢复。治疗效果似乎是通过轴突生长和修复介导的，而不是由于髓鞘特异性 T 细胞的致脑炎能力发生变化所致。沉默 Nogo-A 可能是 MS 患者的一种治疗选择，可预防由免疫介导的轴突损伤引起的永久性功能缺陷。
