Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.
Center for Brain Disorders Research, Capital Mexical University, PR China; Beijing Institute for Brain Disorders, PR China; Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, PR China.
Eur J Pharmacol. 2018 Jul 5;830:128-138. doi: 10.1016/j.ejphar.2018.04.001. Epub 2018 Apr 4.
Cerebral ischemia causes blood-brain barrier (BBB) injury and thus increases the risk of complications secondary to thrombolysis, which limited its clinical application. This study aims to clarify the role and mechanism of salidroside (SALD) in alleviating brain ischemic injury and whether pretreatment of it could improve prognosis of delayed treatment of tissue plasminogen activator (t-PA). Rats were subjected to 3 h of middle cerebral artery occlusion (MCAO) and were intraperitoneally administered with 10, 20 or 40 mg/kg SALD before ischemia. 1.5% 5-triphenyl-2H-tetrazolium chloride (TTC) staining and neurological studies were performed to observe the effectiveness of SALD. The expressions and the distribution of phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) signaling were analyzed. Experiments were further conducted in isolated microvessels and human brain microvascular endothelial cells (HBMECs) to explore the protective mechanism of SALD. Finally, rats were subjected to 6 h of MCAO and 24 h of reperfusion. tPA was given with or without the pretreatment of SALD. Various approaches including gelatin zymography, western blot and immunofluorescence were used to evaluate the effect of this combination therapy. SALD could reduce cerebral ischemic injury and enhance HBMECs viability subjected to OGD. In vivo and in vitro studies showed the mechanism might be related to the activation of PI3K/Akt signaling by phosphorylating Akt on Ser473. Pretreatment of SALD could alleviate BBB injury and improve the outcome of delayed treatment of tPA. These results provide evidence that SALD might be an effective adjuvant to reduce the complications induced by delayed tPA treatment for brain ischemia.
脑缺血导致血脑屏障（BBB）损伤，从而增加溶栓后并发症的风险，限制了其临床应用。本研究旨在阐明红景天苷（SALD）在减轻脑缺血损伤中的作用和机制，以及其预处理是否可以改善组织型纤溶酶原激活剂（t-PA）延迟治疗的预后。大鼠进行 3 小时大脑中动脉闭塞（MCAO），缺血前腹腔内给予 10、20 或 40mg/kg SALD。进行 1.5%5-三苯基-2H-四唑氯化物（TTC）染色和神经学研究，以观察 SALD 的效果。分析磷酸肌醇 3-激酶/蛋白激酶 B（PI3K/Akt）信号的表达和分布。进一步在分离的微血管和人脑微血管内皮细胞（HBMEC）中进行实验，以探讨 SALD 的保护机制。最后，大鼠进行 6 小时 MCAO 和 24 小时再灌注。tPA 与或不与 SALD 的预处理一起给予。采用明胶酶谱、western blot 和免疫荧光等多种方法评价这种联合治疗的效果。SALD 可减轻脑缺血损伤并增强 OGD 后 HBMEC 的活力。体内和体外研究表明，其机制可能与通过磷酸化 Akt Ser473 激活 PI3K/Akt 信号有关。SALD 的预处理可减轻 BBB 损伤并改善 tPA 延迟治疗的预后。这些结果为 SALD 可能是减少脑缺血后延迟 tPA 治疗引起的并发症的有效辅助药物提供了证据。
