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CID1067700, a late endosome GTPase Rab7 receptor antagonist, attenuates brain atrophy, improves neurologic deficits and inhibits reactive astrogliosis in rat ischemic stroke.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-10-12 , DOI: 10.1038/s41401-018-0166-8 Yuan Qin 1 , Yang He 1 , Yong-Ming Zhu 1 , Min Li 1 , Yong Ni 1 , Jin Liu 1 , Hui-Ling Zhang 1
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-10-12 , DOI: 10.1038/s41401-018-0166-8 Yuan Qin 1 , Yang He 1 , Yong-Ming Zhu 1 , Min Li 1 , Yong Ni 1 , Jin Liu 1 , Hui-Ling Zhang 1
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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：
CID1067700 是一种晚期内体 GTPase Rab7 受体拮抗剂，可减轻大鼠缺血性中风的脑萎缩、改善神经功能缺损并抑制反应性星形胶质细胞增生。
越来越多的证据表明，大脑 7 (Rab7) 中与 Ras 相关的内体定位小 GTP 酶会导致脑缺血性脑损伤。在本研究中，我们研究了 Rab7 在缺血性中风诱导的星形胶质细胞增生和神经胶质疤痕形成中的作用。对大鼠进行短暂大脑中动脉闭塞（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糖剥夺和复氧（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，随着时间的推移，Rab7 显着升高，并且 CID 的施用显着下调胶质疤痕标记物，例如胶质纤维酸性蛋白 (GFAP)、神经聚糖和磷酸聚糖。此外，CID 的施用显着减轻了 tMCAO 大鼠的脑萎缩并改善了神经功能缺损，并保护星形胶质细胞免受 OGD/Re 诱导的损伤。此外，在 OGD/Re 或 tMCAO 损伤后，CID 下调星形胶质细胞中 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 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。综上所述，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疤痕的形成。 CID 给药可通过减少组织蛋白酶 B 从溶酶体激活和释放到细胞质中来减轻脑萎缩，改善神经功能缺陷，并抑制缺血性中风后星形胶质细胞增生和神经胶质疤痕形成。
更新日期：2019-01-26
中文翻译：
CID1067700 是一种晚期内体 GTPase Rab7 受体拮抗剂，可减轻大鼠缺血性中风的脑萎缩、改善神经功能缺损并抑制反应性星形胶质细胞增生。
越来越多的证据表明，大脑 7 (Rab7) 中与 Ras 相关的内体定位小 GTP 酶会导致脑缺血性脑损伤。在本研究中，我们研究了 Rab7 在缺血性中风诱导的星形胶质细胞增生和神经胶质疤痕形成中的作用。对大鼠进行短暂大脑中动脉闭塞（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糖剥夺和复氧（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，随着时间的推移，Rab7 显着升高，并且 CID 的施用显着下调胶质疤痕标记物，例如胶质纤维酸性蛋白 (GFAP)、神经聚糖和磷酸聚糖。此外，CID 的施用显着减轻了 tMCAO 大鼠的脑萎缩并改善了神经功能缺损，并保护星形胶质细胞免受 OGD/Re 诱导的损伤。此外，在 OGD/Re 或 tMCAO 损伤后，CID 下调星形胶质细胞中 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 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。综上所述，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疤痕的形成。 CID 给药可通过减少组织蛋白酶 B 从溶酶体激活和释放到细胞质中来减轻脑萎缩，改善神经功能缺陷，并抑制缺血性中风后星形胶质细胞增生和神经胶质疤痕形成。
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