From the Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China (S.M., Y.L.).
Pittsburgh Institute of Brain Disorders and Recovery, and Department of Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
Stroke. 2018 Oct;49(10):2453-2463. doi: 10.1161/STROKEAHA.118.021452.
Background and Purpose- Type 2 diabetes mellitus (T2DM) is a major comorbidity that exacerbates ischemic brain injury and worsens functional outcome after stroke. T2DM is known to aggravate white matter (WM) impairment, but the underlying mechanism is not completely understood. This study was designed to test the hypothesis that T2DM impedes poststroke WM recovery by suppressing both oligodendrogenesis and beneficial microglia/macrophage responses. Methods- Permanent distal middle cerebral artery occlusion was performed in wild-type, homozygous diabetic db/db, and heterozygous db/+ mice. The adhesive removal, open field, and Morris water maze tests were used to assess neurobehavioral outcomes. Neuronal tissue loss, WM damage, oligodendrogenesis, and microglia/macrophage responses were evaluated up to 35 days after stroke. The functional integrity of WM was measured by electrophysiology. Primary microglia-oligodendrocyte cocultures were used for additional mechanistic studies. Results- T2DM exacerbated structural damage and impaired conduction of compound action potentials in WM 35 days after stroke. The deterioration in WM integrity correlated with poor sensorimotor performance. Furthermore, T2DM impaired the proliferation of oligodendrocyte precursor cells and the generation of new myelinating oligodendrocytes. T2DM also promoted a shift of microglia/macrophage phenotype toward the proinflammatory modality. Coculture studies confirmed that microglia/macrophage polarization toward the proinflammatory phenotype under high glucose conditions suppressed oligodendrocyte precursor cell differentiation. Conclusions- Deterioration of WM integrity and impairments in oligodendrogenesis after stroke are associated with poor long-term functional outcomes in experimental diabetes mellitus. High glucose concentrations may shift microglia/macrophage polarization toward a proinflammatory phenotype, significantly impairing oligodendrocyte precursor cell differentiation and WM repair.
背景与目的-2 型糖尿病（T2DM）是一种主要的合并症，可加重缺血性脑损伤并使中风后的功能预后恶化。已知 T2DM 会加重白质（WM）损伤，但具体的发病机制尚不完全清楚。本研究旨在验证 T2DM 通过抑制少突胶质细胞生成和有益的小胶质细胞/巨噬细胞反应来阻碍中风后 WM 恢复的假说。方法-在野生型、纯合子糖尿病 db/db 和杂合子 db/+小鼠中进行永久性大脑中动脉远端闭塞。采用粘取物移除、旷场和 Morris 水迷宫试验来评估神经行为学结果。评估神经元组织丢失、WM 损伤、少突胶质细胞生成和小胶质细胞/巨噬细胞反应，直到中风后 35 天。通过电生理学来测量 WM 的功能完整性。将原代小胶质细胞-少突胶质细胞共培养物用于进一步的机制研究。结果-T2DM 使中风后 35 天 WM 的结构损伤加剧，并损害了复合动作电位的传导。WM 完整性的恶化与感觉运动功能不良相关。此外，T2DM 还损害了少突胶质细胞前体细胞的增殖和新生髓鞘形成的少突胶质细胞的生成。T2DM 还促使小胶质细胞/巨噬细胞表型向促炎模式转变。共培养研究证实，在高葡萄糖条件下，小胶质细胞/巨噬细胞向促炎表型极化会抑制少突胶质细胞前体细胞的分化。结论-WM 完整性恶化和中风后少突胶质细胞生成受损与实验性糖尿病中不良的长期功能预后相关。高葡萄糖浓度可能使小胶质细胞/巨噬细胞向促炎表型极化，从而显著损害少突胶质细胞前体细胞的分化和 WM 修复。
