CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Graduate School, Beijing, China.
Glia. 2019 Jul;67(7):1320-1332. doi: 10.1002/glia.23606. Epub 2019 Feb 28.
Oligodendrocytes (OLs) are the myelinating glia of the central nervous system. Injury to OLs causes myelin loss. In demyelinating diseases, such as multiple sclerosis, the remyelination is hindered principally due to a failure of the oligodendrocyte precursor cells (OPCs) to differentiate into mature OLs. To identify inducers of OPC to OL differentiation, a high-throughput screening based on myelin basic protein expression using neural progenitor cells-derived OPCs has been performed and, PD0325901-an MEK (MAPK kinase) inhibitor-is found to significantly enhance OPC to OL differentiation in a dose- and time-dependent manner. Other MEK inhibitors also display similar effect, indicating blockade of MAPK-ERK signaling is sufficient to induce OPC differentiation into OLs. PD0325901 facilitates the formation of myelin sheaths in OPC-neuron co-culture in vitro. And in experimental autoimmune encephalomyelitis model and cuprizone-induced demyelination model, PD0325901 displays significant therapeutic effect by promoting myelin regeneration. Our results suggest that targeting the MAPK-ERK pathway might be an intriguing way to develop new therapies for demyelinating diseases.
少突胶质细胞（OLs）是中枢神经系统的髓鞘形成胶质细胞。OLs 的损伤会导致髓鞘丢失。在脱髓鞘疾病中，如多发性硬化症，髓鞘的再形成主要受到少突胶质前体细胞（OPCs）向成熟 OL 分化失败的阻碍。为了鉴定诱导 OPC 向 OL 分化的诱导物，我们使用神经祖细胞衍生的 OPC 进行了基于髓鞘碱性蛋白表达的高通量筛选，发现 PD0325901（一种 MEK（MAPK 激酶）抑制剂）可显著增强 OPC 向 OL 分化，呈剂量和时间依赖性。其他 MEK 抑制剂也显示出类似的效果，表明阻断 MAPK-ERK 信号足以诱导 OPC 分化为 OL。PD0325901 促进了体外 OPC-神经元共培养中髓鞘鞘的形成。在实验性自身免疫性脑脊髓炎模型和杯状蛋白诱导的脱髓鞘模型中，PD0325901 通过促进髓鞘再生显示出显著的治疗效果。我们的结果表明，靶向 MAPK-ERK 通路可能是开发脱髓鞘疾病新疗法的一种有趣方法。
