Abstract：
Demyelination of corticospinal tract neurons contributes to long-term disability after cortical stroke. Nonetheless, poststroke myelin loss has not been addressed as a therapeutic target, so far. We hypothesized that an antibody-mediated inhibition of the Nogo receptor-interacting protein (LINGO-1, leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein) may counteract myelin loss, enhance remyelination and axonal growth, and thus promote functional recovery following stroke. To verify this hypothesis, mice were subjected to photothrombotic stroke and received either an antibody against LINGO-1 (n = 19) or a control treatment (n = 18). Behavioral tests were performed to assess the effects of anti-LINGO-1 treatment on the functional recovery. Seven weeks after stroke, immunohistochemical analyses were performed to analyze the effect of anti-LINGO-1 treatment on myelination and axonal loss of corticospinal tract neurons, proliferation of oligodendrocytes and neurogenesis. Anti-LINGO-1 treatment resulted in significantly improved functional recovery (p < 0.0001, repeated measures analysis of variance), and increased neurogenesis in the hippocampus and subventricular zone of the ipsilateral hemisphere (p = 0.0094 and p = 0.032, t-test). Notably, we observed a significant increase in myelin (p = 0.0295, t-test), platelet-derived growth factor receptor α-positive oligodendrocyte precursor cells (p = 0.0356, t-test) and myelinating adenomatous polyposis coli-positive cells within the ipsilateral internal capsule of anti-LINGO-1-treated mice (p = 0.0021, t-test). In conclusion, we identified anti-LINGO-1 as the first neuroregenerative treatment that counteracts poststroke demyelination of corticospinal tract neurons, presumably by increased proliferation of myelin precursor cells, and thereby improves functional recovery. Most importantly, our study presents myelin loss as a novel therapeutic target following stroke.
摘要：
皮质脊髓束神经元脱髓鞘有助于皮质卒中后的长期残疾。尽管如此，卒中后髓鞘丢失尚未作为治疗靶点,到目前为止。我们假设抗体介导的Nogo受体相互作用蛋白（LINGO-1，富含亮氨酸的重复序列和含有免疫球蛋白结构域的Nogo受体相互作用蛋白）的抑制可能会抵消髓鞘丢失，增强髓鞘再生和轴突生长，从而促进中风后的功能恢复。为了验证这个假设，对小鼠进行光血栓形成性中风,并接受抗LINGO-1抗体(n=19)或对照治疗(n=18).进行行为测试以评估抗LINGO-1治疗对功能恢复的影响。中风后七周,进行免疫组织化学分析以分析抗LINGO-1治疗对皮质脊髓束神经元髓鞘形成和轴突丢失的影响，少突胶质细胞的增殖和神经发生。抗LINGO-1治疗导致显著改善的功能恢复(p<0.0001,重复测量方差分析),同侧半球海马和脑室下区的神经发生增加（p=0.0094和p=0.032，t检验）。值得注意的是,我们观察到髓磷脂的显着增加（p=0.0295，t检验），抗LINGO-1治疗小鼠同侧内囊内的血小板衍生生长因子受体α阳性少突胶质细胞前体细胞（p=0.0356，t检验）和髓鞘腺瘤性结肠息肉阳性细胞（p=0.0021，t检验）。总之,我们确定抗LINGO-1是第一个对抗卒中后皮质脊髓束神经元脱髓鞘的神经再生治疗，可能是由于髓鞘前体细胞的增殖增加，从而提高功能恢复。最重要的是,我们的研究将髓磷脂丢失作为卒中后的一个新的治疗靶点.
