Increasing evidence suggests that Ras-related in brain 7 (Rab7), an endosome-localized small GTPase contributes to cerebral ischemic brain injury. In the present study, we investigated the role of Rab7 in ischemic stroke-induced formation of astrogliosis and glial scar. Rats were subjected to transient middle cerebral artery occlusion (tMCAO); the rats were injected with the Rab7 receptor antagonist CID1067700 (CID). Primary astrocytes were subjected to an oxygen and glucose deprivation and reoxygenation (OGD/Re) procedure; CID was added to the cell culture media. We found that Rab7 was significantly elevated over time in both the in vivo and in vitro astrocytic injury models, and administration of CID significantly down-regulated the glial scar markers such as glial fibillary acidic protein (GFAP), neurocan and phosphacan. Moreover, administration of CID significantly attenuated the brain atrophy and improved neurologic deficits in tMCAO rats, and protected astrocytes against OGD/Re-induced injury. Further, CID downregulated the protein levels of Lamp1 and active cathepsin B in astrocytes after OGD/Re or tMCAO injury; CID inhibited the co-localization of cathepsin B and Rab7, Lamp1 and Rab7; CID decreased OGD/Re-induced increase in lysosomal membrane permeability and blocked OGD/Re-induced release of cathepsin B from the lysosome into the cytoplasm in astrocytes. Taken together, these results suggest that Rab7 is involved in ischemic stroke-induced formation of astrogliosis and glial scar. CID administration attenuates brain atrophy and improves neurologic deficits and inhibits astrogliosis and glial scar formation after ischemic stroke via reducing the activation and release of cathepsin B from the lysosome into the cytoplasm.

中文翻译：

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CID1067700是晚期内体GTPase Rab7受体拮抗剂，可减轻脑萎缩，改善神经功能缺损并抑制大鼠缺血性中风的反应性星形胶质变。

越来越多的证据表明，脑内Ras相关蛋白7（Rab7）是一种内体定位的小GTP酶，可导致脑缺血性脑损伤。在本研究中，我们调查了Rab7在缺血性中风诱导的星形胶质细胞增生和神经胶质瘢痕形成中的作用。大鼠经历短暂的大脑中动脉闭塞（tMCAO）；给大鼠注射Rab7受体拮抗剂CID1067700（CID）。对原代星形胶质细胞进行氧和葡萄糖的剥夺和复氧（OGD / Re）程序；将CID添加到细胞培养基中。我们发现在体内和体外星形胶质细胞损伤模型中，Rab7随时间显着升高，而CID的施用显着下调了神经胶质瘢痕标志物，例如神经胶质原纤维酸性蛋白（GFAP），神经胶质蛋白和磷酰胺。而且，给予CID可以显着减轻tMCAO大鼠的脑萎缩并改善神经功能缺损，并保护星形胶质细胞免受OGD / Re诱导的损伤。此外，CID下调了OGD / Re或tMCAO损伤后星形胶质细胞中Lamp1和活性组织蛋白酶B的蛋白水平。CID抑制组织蛋白酶B和Rab7，Lamp1和Rab7的共定位；CID降低了OGD / Re诱导的溶酶体膜通透性增加，并阻止了OGD / Re诱导的组织蛋白酶B从溶酶体释放到星形胶质细胞的细胞质中。两者合计，这些结果表明Rab7参与缺血性中风诱导的星形胶质细胞增生和神经胶质瘢痕的形成。