Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Exp Neurol. 2020 Dec;334:113454. doi: 10.1016/j.expneurol.2020.113454. Epub 2020 Aug 30.
Individuals with demyelinating diseases often experience difficulties during social interactions that are not well studied in preclinical models. Here, we describe a novel juvenile focal corpus callosum demyelination murine model exhibiting a social interaction deficit. Using this preclinical murine demyelination model, we discover that application of metformin, an FDA-approved drug, in this model promotes oligodendrocyte regeneration and remyelination and improves the social interaction. This beneficial effect of metformin acts through stimulating Ser436 phosphorylation in CBP, a histone acetyltransferase. In addition, we found that metformin acts through two distinct molecular pathways to enhance oligodendrocyte precursor (OPC) proliferation and differentiation, respectively. Metformin enhances OPC proliferation through early-stage autophagy inhibition, while metformin promotes OPC differentiation into mature oligodendrocytes through activating CBP Ser436 phosphorylation. In summary, we identify that metformin is a promising remyelinating agent to improve juvenile demyelination-associated social interaction deficits by promoting oligodendrocyte regeneration and remyelination.
脱髓鞘疾病患者在社交互动中经常会遇到困难，但在临床前模型中对此研究甚少。在这里，我们描述了一种新型幼年局灶性胼胝体脱髓鞘的小鼠模型，该模型表现出社交互动缺陷。使用这种临床前的脱髓鞘小鼠模型，我们发现二甲双胍（一种 FDA 批准的药物）在该模型中的应用可促进少突胶质细胞的再生和髓鞘形成，并改善社交互动。二甲双胍的这种有益作用是通过刺激 CBP 的 Ser436 磷酸化来实现的，CBP 是一种组蛋白乙酰转移酶。此外，我们发现二甲双胍通过两种不同的分子途径分别增强少突胶质前体细胞（OPC）的增殖和分化。二甲双胍通过早期自噬抑制来增强 OPC 的增殖，而二甲双胍通过激活 CBP Ser436 磷酸化来促进 OPC 分化为成熟的少突胶质细胞。总之，我们确定二甲双胍是一种有前途的髓鞘修复药物，可通过促进少突胶质细胞的再生和髓鞘形成来改善与幼年脱髓鞘相关的社交互动缺陷。
