罗格列酮促进局灶性脑缺血后白质完整性及长期功能恢复。
Rosiglitazone Promotes White Matter Integrity and Long-Term Functional Recovery After Focal Cerebral Ischemia.
作者信息
Han Lijuan, Cai Wei, Mao Leilei, Liu Jia, Li Peiying, Leak Rehana K, Xu Yun, Hu Xiaoming, Chen Jun
机构信息
From the Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P.R. China (L.H., Y.X.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (L.H., W.C., L.M., X.H., J.C.); State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., P.L., X.H., J.C.); Department of Neurology, Multiple Sclerosis Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China (W.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
出版信息
Stroke. 2015 Sep;46(9):2628-36. doi: 10.1161/STROKEAHA.115.010091. Epub 2015 Aug 4.
BACKGROUND AND PURPOSE
Oligodendrogenesis is essential for white matter repair after stroke. Although agonists of peroxisome proliferator-activated receptors 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 peroxisome proliferator-activated receptors γ agonist rosiglitazone enhances oligodendrogenesis and improves long-term white matter integrity after ischemia/reperfusion.
METHODS
Male adult C57/BL6 mice (25-30 g) were subjected to 60-minute middle cerebral artery occlusion and reperfusion. Rosiglitazone (3 mg/kg) was injected intraperitoneally once daily for 14 days beginning 2 hours after reperfusion. Sensorimotor and cognitive functions were evaluated ≤21 days after middle cerebral artery occlusion. 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 adenomatous polyposis coli(+) oligodendrocytes. Mixed glial cultures were used to confirm the effect of rosiglitazone on oligodendrocyte differentiation and microglial polarization.
RESULTS
Rosiglitazone significantly reduced brain tissue loss, ameliorated white matter injury, and improved sensorimotor and cognitive functions for at least 21 days after middle cerebral artery occlusion. Rosiglitazone enhanced OPC proliferation and increased the numbers of newly generated mature oligodendrocytes after middle cerebral artery occlusion. 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.
CONCLUSIONS
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.
背景与目的
少突胶质细胞生成对于中风后的白质修复至关重要。尽管过氧化物酶体增殖物激活受体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能扩展至白质保护。本研究检验了过氧化物酶体增殖物激活受体γ激动剂罗格列酮可增强少突胶质细胞生成并改善缺血/再灌注后长期白质完整性的假说。
方法
雄性成年C57/BL6小鼠（25 - 30克）接受60分钟大脑中动脉闭塞及再灌注。从再灌注后2小时开始，罗格列酮（3毫克/千克）每天腹腔注射1次，共14天。在大脑中动脉闭塞后≤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、髓鞘损失和小胶质细胞激活。注射溴脱氧尿苷以测量增殖的NG2(+)少突胶质细胞前体细胞（OPC）和新生成的腺瘤性息肉病蛋白(+)少突胶质细胞。使用混合胶质细胞培养来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。
结果
罗格列酮显著减少脑组织损失，改善白质损伤，并在大脑中动脉闭塞后至少21天改善感觉运动和认知功能。罗格列酮增强了OPC增殖，并增加了大脑中动脉闭塞后新生成的成熟少突胶质细胞数量。罗格列酮治疗还减少了中风后Iba1(+)/CD16(+) M1小胶质细胞数量，并增加了Iba1(+)/CD206(+) M2小胶质细胞数量。胶质细胞培养实验证实罗格列酮可能通过促进小胶质细胞M2极化来促进少突胶质细胞分化。
结论
罗格列酮治疗至少部分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表型极化来改善脑缺血后的长期白质完整性。
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