Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Guangdong Pharmaceutical University, Guangzhou, 510006, China.
Acta Pharmacol Sin. 2021 Mar;42(3):370-381. doi: 10.1038/s41401-020-00568-2. Epub 2020 Dec 10.
Stroke is an acute cerebrovascular disease caused by ruptured or blocked blood vessels. For the prevention of ischemic stroke, the coagulation state of blood and cerebrovascular protection should be considered. Our previous study has shown that salvianolic acid A (SAA), which is a water-soluble component from the root of Salvia Miltiorrhiza Bge, prevents thrombosis with a mild inhibitory effect on platelet aggregation. In this study we investigated the preventive effects of SAA on cerebrovascular endothelial injury caused by ischemia in vivo and oxygen-glucose deprivation (OGD) in vitro, and explored the underlying mechanisms. An autologous thrombus stroke model was established in SD rats by electrocoagulation. SAA (10 mg/kg) was orally administered twice a day for 5 days before the operation. The rats were sacrificed at 24 h after the operation. We showed that pretreatment with SAA significantly improved the neurological deficits, intracerebral hemorrhage, BBB disruption, and vascular endothelial dysfunction as compared with model group. In human brain microvascular endothelial cells (HBMECs), pretreatment with SAA (10 μM) significantly inhibited OGD-induced cell viability reduction and degradation of tight junction proteins (ZO-1, occludin, claudin-5). Furthermore, we found that SAA inhibited the upregulation of Src signaling pathway in vivo and vitro and reversed the increased expression of matrix metalloproteinases (MMPs) after ischemic stroke. In conclusion, our results suggest that SAA protects cerebrovascular endothelial cells against ischemia and OGD injury via suppressing Src signaling pathway. These findings show that pretreatment with SAA is a potential therapeutic strategy for the prevention of ischemic stroke.
中风是一种由血管破裂或阻塞引起的急性脑血管病。为了预防缺血性中风，应该考虑血液的凝血状态和脑血管保护。我们之前的研究表明，丹参水溶性成分丹参酸 A（SAA）具有轻度抑制血小板聚集的抗血栓作用。本研究旨在探讨 SAA 对体内缺血性脑血管内皮损伤和体外氧葡萄糖剥夺（OGD）的预防作用，并探讨其潜在机制。通过电凝法在 SD 大鼠中建立自体血栓性中风模型。在手术前每天口服 SAA（10mg/kg）两次，共 5 天。手术后 24 小时处死大鼠。结果表明，与模型组相比，SAA 预处理可显著改善神经功能缺损、脑出血、血脑屏障破坏和血管内皮功能障碍。在人脑血管内皮细胞（HBMEC）中，SAA（10μM）预处理可显著抑制 OGD 诱导的细胞活力降低和紧密连接蛋白（ZO-1、occludin、claudin-5）降解。此外，我们发现 SAA 可抑制体内和体外 Src 信号通路的上调，并逆转缺血性中风后基质金属蛋白酶（MMPs）的表达增加。总之，我们的研究结果表明，SAA 通过抑制 Src 信号通路来保护脑血管内皮细胞免受缺血和 OGD 损伤。这些发现表明，SAA 预处理是预防缺血性中风的一种潜在治疗策略。
