Abstract：
Accumulating evidences suggest a strong correlation between metabolic changes and neurodegeneration in CNS demyelinating diseases such as multiple sclerosis (MS). Biotin, an essential cofactor for five carboxylases, is expressed by oligodendrocytes and involved in fatty acid synthesis and energy production. The metabolic effect of biotin or high-dose-biotin (MD1003) has been reported on rodent oligodendrocytes in vitro, and in neurodegenerative or demyelinating animal models. However, clinical studies, showed mild or no beneficial effect of MD1003 in amyotrophic lateral sclerosis (ALS) or MS. Here, we took advantage of a mouse model of myelin deficiency to study the effects of MD1003 on the behavior of murine and grafted human oligodendrocytes in vivo. We show that MD1003 increases the number and the differentiation potential of endogenous murine oligodendroglia over time. Moreover, the levels of MD1003 are increased in the plasma and brain of pups born to treated mothers, indicating that MD1003 can pass through the mother\'s milk. The histological analysis of the grafted animals shows that MD1003 increased proliferation and accelerates differentiation of human oligodendroglia, but without enhancing their myelination potential. These findings provide important insights into the role of MD1003 on murine and human oligodendrocyte maturation/myelination that may explain the mitigated outcome of ALS/MS clinical trials.
摘要：
越来越多的证据表明，代谢变化与中枢神经系统脱髓鞘疾病如多发性硬化症（MS）中的神经变性之间存在很强的相关性。生物素,五种羧化酶的必需辅因子，由少突胶质细胞表达并参与脂肪酸合成和能量产生。已经报道了生物素或高剂量生物素（MD1003）在体外对啮齿动物少突胶质细胞的代谢作用，和神经退行性或脱髓鞘动物模型。然而,临床研究,MD1003在肌萎缩侧索硬化症（ALS）或MS中显示出轻度或无有益作用。这里,我们利用小鼠髓鞘缺乏模型来研究MD1003对小鼠和移植的人少突胶质细胞在体内行为的影响。我们显示MD1003随时间增加内源性鼠少突胶质细胞的数量和分化潜力。此外，MD1003的水平在接受治疗的母亲出生的幼崽的血浆和大脑中增加，表明MD1003可以通过母亲的牛奶。移植动物的组织学分析表明，MD1003增加了人少突胶质细胞的增殖并加速了分化，但没有增强它们的髓鞘形成潜力。这些发现为MD1003对小鼠和人类少突胶质细胞成熟/髓鞘形成的作用提供了重要的见解，这可能解释了ALS/MS临床试验的缓解结果。
