Rosiglitazone Promotes White Matter Integrity and Long-Term Functional Recovery After Focal Cerebral Ischemia.
Rosiglitazone Promotes White Matter Integrity and Long-Term Functional Recovery After Focal Cerebral Ischemia.
复制标题
罗格列酮促进局灶性脑缺血后白质完整性和长期功能恢复
DOI：
10.1161/strokeaha.115.010091
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发表时间：
2015-09
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：
Han L;Cai W;Mao L;Liu J;Li P;Leak RK;Xu Y;Hu X;Chen J
脑卒中后白色物质的修复需要少突胶质细胞的生成。虽然过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂在脑缺血模型中具有神经保护作用，但尚不清楚这种作用是否延伸到白色保护。本研究验证了这样的假设，即PPAR-γ激动剂罗格列酮可增强缺血/再灌注后少突胶质细胞的生成并改善长期白色物质的完整性。雄性成年C57/BL 6小鼠（25- 30 g）经历60分钟的大脑中动脉闭塞（MCAO）和再灌注。再灌注后2 h开始腹腔注射罗格列酮（3 mg/kg），每日1次，共14 d。在MCAO后21天评估感觉运动和认知功能。免疫染色用于评估梗死体积、髓鞘丢失和小胶质细胞活化。注射溴脱氧尿苷（BrdU）用于测量增殖的NG 2+少突胶质细胞前体细胞（OPC）和新产生的APC+少突胶质细胞。混合胶质细胞培养用于证实罗格列酮对少突胶质细胞分化和小胶质细胞极化的影响。罗格列酮可显著减少脑组织丢失，改善白色物质损伤，并改善MCAO后至少21天的感觉运动和认知功能。罗格列酮促进OPC增殖，增加MCAO后新生成的成熟少突胶质细胞的数量。罗格列酮治疗还减少了卒中后Iba 1 +/CD 16 + M1小胶质细胞的数量，增加了Iba 1 +/CD 206 + M2小胶质细胞的数量。胶质细胞培养实验证实，罗格列酮促进少突胶质细胞分化，可能是通过促进小胶质细胞M2极化。罗格列酮治疗改善脑缺血后长期白色物质的完整性，至少部分是通过促进少突胶质细胞生成和促进小胶质细胞向有益的M2表型极化。
Oligodendrogenesis is essential for white matter repair after stroke. Although agonists of peroxisome proliferator-activated receptors γ (PPAR-γ) confer neuroprotection in models of cerebral ischemia, it is not known whether this effect extends to white matter protection. This study tested the hypothesis that the PPAR-γ agonist rosiglitazone enhances oligodendrogenesis and improves long-term white matter integrity after ischemia/reperfusion. Male adult C57/BL6 mice (25-30g) were subjected to 60 minutes middle cerebral artery occlusion (MCAO) and reperfusion. Rosiglitazone (3mg/kg) was injected intraperitoneally once daily for 14d beginning 2 hours after reperfusion. Sensorimotor and cognitive functions were evaluated up to 21d after MCAO. Immunostaining was used to assess infarct volume, myelin loss, and microglial activation. Bromodeoxyuridine (BrdU) was injected for measurements of proliferating NG2+ oligodendrocyte precursor cells (OPCs) and newly generated APC+ oligodendrocytes. Mixed glial cultures were used to confirm the effect of rosiglitazone on oligodendrocyte differentiation and microglial polarization. Rosiglitazone significantly reduced brain tissue loss, ameliorated white matter injury, and improved sensorimotor and cognitive functions for at least 21d after MCAO. Rosiglitazone enhanced OPC proliferation and increased the numbers of newly generated mature oligodendrocytes after MCAO. Rosiglitazone treatment also reduced the numbers of Iba1+/CD16+ M1 microglia and increased the numbers of Iba1+/CD206+ M2 microglia after stroke. Glial culture experiments confirmed that rosiglitazone promoted oligodendrocyte differentiation, perhaps by promoting microglial M2 polarization. Rosiglitazone treatment improves long-term white matter integrity after cerebral ischemia, at least in part by promoting oligodendrogenesis and facilitating microglial polarization toward the beneficial M2 phenotype.