Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits After Cerebral Ischemia.
Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits After Cerebral Ischemia.
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DOI：
10.1161/strokeaha.118.021452
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发表时间：
2018-10
期刊：
影响因子：
8.3
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Ma S;Wang J;Wang Y;Dai X;Xu F;Gao X;Johnson J;Xu N;Leak RK;Hu X;Luo Y;Chen J
2型糖尿病（T2 DM）是加重缺血性脑损伤和脑卒中后功能结局的主要合并症。已知2型糖尿病会加重白色损害，但其潜在机制尚未完全了解。本研究旨在检验T2 DM通过抑制少突胶质细胞生成和有益的小胶质细胞/巨噬细胞反应阻碍卒中后白色物质恢复的假设。在野生型、纯合子糖尿病db/db和杂合子db/+小鼠中进行永久性远端大脑中动脉闭塞。使用粘合剂去除、旷场和Morris水迷宫测试来评估神经行为结果。在卒中后35天内评估神经元组织损失、白色物质损伤、少突胶质细胞生成和小胶质细胞/巨噬细胞反应。通过电生理学测量白色物质的功能完整性。原代小胶质细胞-少突胶质细胞共培养物用于另外的机制研究。中风后35天，T2 DM加剧了结构损伤并损害了白色物质复合动作电位的传导。白色物质完整性的恶化与感觉运动表现差相关。此外，2型糖尿病损害了少突胶质前体细胞（OPC）的增殖和新的髓鞘少突胶质细胞的产生。T2 DM还促进了小胶质细胞/巨噬细胞表型向促炎模式的转变。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抑制OPC分化。脑卒中后白色物质完整性的恶化和少突胶质细胞的损伤与实验性糖尿病患者的长期功能预后不良相关。高葡萄糖浓度可能使小胶质细胞/巨噬细胞极化向促炎表型转变，显著损害OPC分化和白色修复。
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 impairment but the underlying mechanism is not completely understood. This study was designed to test the hypothesis that T2DM impedes post-stroke white matter recovery by suppressing both oligodendrogenesis and beneficial microglia/macrophage responses. 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, white matter damage, oligodendrogenesis, and microglia/macrophage responses were evaluated up to 35d after stroke. The functional integrity of white matter was measured by electrophysiology. Primary microglia-oligodendrocyte co-cultures were used for additional mechanistic studies. T2DM exacerbated structural damage and impaired conduction of compound action potentials in white matter 35d after stroke. The deterioration in white matter integrity correlated with poor sensorimotor performance. Furthermore, T2DM impaired the proliferation of oligodendrocyte precursor cells (OPCs) and the generation of new myelinating oligodendrocytes. T2DM also promoted a shift of microglia/macrophage phenotype toward the pro-inflammatory modality. Co-culture studies confirmed that microglia/macrophage polarization toward the pro-inflammatory phenotype under high glucose conditions suppressed OPC differentiation. Deterioration of white matter 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 pro-inflammatory phenotype, significantly impairing OPC differentiation and white matter repair.