Zhu Yong-Ming, Gao Xue, Ni Yong, Li Wei, Kent Thomas A, Qiao Shi-Gang, Wang Chen, Xu Xiao-Xuan, Zhang Hui-Ling
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, and Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China.
Stroke Outcomes Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX, United States; and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston 77030, TX, United States.
Neuroscience. 2017 Jul 25;356:125-141. doi: 10.1016/j.neuroscience.2017.05.004. Epub 2017 May 10.
Cerebral ischemia leads to astrocyte's activation and glial scar formation. Glial scar can inhibit axonal regeneration during the recovery phase. It has demonstrated that sevoflurane has neuroprotective effects against ischemic stroke, but its effects on ischemia-induced formation of astrogliosis and glial scar are unknown. This study was designed to investigate the effect of sevoflurane postconditioning on astrogliosis and glial scar formation in ischemic stroke model both in vivo and in vitro. The results showed that 2.5% of sevoflurane postconditioning could significantly reduce infarction volume and improve neurologic deficits. And it could also decrease the expression of the glial scar marker glial fibrillary acidic protein (GFAP), neurocan and phosphacan in the peri-infarct region and markedly reduce the thickness of glial scar after ischemia/reperfusion (I/R). Consistent with the in vivo data, in the oxygen and glucose deprivation/reoxygenation (OGD/Re) model, sevoflurane postconditioning could protect astrocyte against OGD/Re-induced injury, decrease the expression of GFAP, neurocan and phosphacan. Further studies demonstrated that sevoflurane postconditioning could down-regulate the expression of Lamp1 and active cathepsin B, and block I/R or OGD/Re-induced release of cathepsin B from the lysosomes into cytoplasm. In order to confirm whether inhibition of cathepsin B could attenuate the formation of glial scar, we used cathepsin B inhibitor CA-074Me as a positive control. The results showed that inhibition of cathepsin B could decrease the expression of GFAP, neurocan and phosphacan. Taken together, sevoflurane postconditioning can attenuate astrogliosis and glial scar formation after ischemic stroke, associating with inhibition of the activation and release of lysosomal cathepsin B.
脑缺血会导致星形胶质细胞活化和胶质瘢痕形成。胶质瘢痕可在恢复阶段抑制轴突再生。已证明七氟醚对缺血性中风具有神经保护作用，但其对缺血诱导的星形胶质细胞增生和胶质瘢痕形成的影响尚不清楚。本研究旨在探讨七氟醚后处理对体内外缺血性中风模型中星形胶质细胞增生和胶质瘢痕形成的影响。结果表明，2.5%的七氟醚后处理可显著减少梗死体积并改善神经功能缺损。它还可降低梗死周边区胶质瘢痕标志物胶质纤维酸性蛋白（GFAP）、神经黏蛋白和磷蛋白聚糖的表达，并在缺血/再灌注（I/R）后显著减小胶质瘢痕的厚度。与体内数据一致，在氧糖剥夺/复氧（OGD/Re）模型中，七氟醚后处理可保护星形胶质细胞免受OGD/Re诱导的损伤，降低GFAP、神经黏蛋白和磷蛋白聚糖的表达。进一步研究表明，七氟醚后处理可下调溶酶体相关膜蛋白1（Lamp1）和活性组织蛋白酶B的表达，并阻断I/R或OGD/Re诱导的组织蛋白酶B从溶酶体释放到细胞质中。为了证实抑制组织蛋白酶B是否能减轻胶质瘢痕的形成，我们使用组织蛋白酶B抑制剂CA-074Me作为阳性对照。结果表明，抑制组织蛋白酶B可降低GFAP、神经黏蛋白和磷蛋白聚糖的表达。综上所述，七氟醚后处理可减轻缺血性中风后的星形胶质细胞增生和胶质瘢痕形成，这与抑制溶酶体组织蛋白酶B的活化和释放有关。
