1 Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhengjiang 310016, China.
Am J Chin Med. 2018;46(6):1225-1241. doi: 10.1142/S0192415X18500647. Epub 2018 Aug 27.
Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease with few effective pharmacotherapies available. Salvia miltiorrhiza, a traditional Chinese medicinal herb, has been widely used to treat cardiovascular diseases for centuries. Recent studies have demonstrated that magnesium lithospermate B (MLB), a bioactive ingredient extracted from Salvia miltiorrhiza, exerts neuroprotective effects in several central nervous system insults. However, little is known about the role of MLB in SAH-induced brain injury and the exact molecular mechanism. In the current study, we studied the neuroprotective effects of MLB in SAH and explored the potential mechanism. Adult male Sprague-Dawley rats were subjected to an endovascular perforation process to produce an SAH model. MLB was administrated intraperitoneally at 30[Formula: see text]min after SAH with a dose of 25[Formula: see text]mg/kg or 50[Formula: see text]mg/kg. We found that administration of MLB significantly attenuated brain edema and neurological deficits after SAH. In addition, immunofluorescence staining demonstrated that MLB dose-dependently inhibited the activation of microglia and reduced neuronal apoptosis. Western blot analysis showed that MLB decreased the expression of inflammatory cytokine TNF-[Formula: see text] and pro-apoptotic protein cleaved caspase-3. More importantly, MLB increased the expression of SIRT1, while inhibited the acetylation of NF-[Formula: see text]B. Furthermore, pretreatment with sirtinol (a selective inhibitor of SIRT1) reversed all the aforementioned effects of MLB after SAH. In conclusion, our results indicated that MLB exerted robust neuroprotective effects against SAH via suppressing neuroinflammation and apoptosis. These neuroprotective effects of MLB against SAH might be exerted via regulating the SIRT1/NF-[Formula: see text]B pathway. MLB or the SIRT1/NF-[Formula: see text]B pathway could be a novel and promising therapeutic strategy for SAH management.
蛛网膜下腔出血 (SAH) 是一种严重的脑血管疾病，目前可用的治疗方法有限。丹参，一种传统的中药，几个世纪以来一直被用于治疗心血管疾病。最近的研究表明，丹参中的一种生物活性成分丹参素 B 镁盐 (MLB) 在几种中枢神经系统损伤中具有神经保护作用。然而，关于 MLB 在 SAH 诱导的脑损伤中的作用及其确切的分子机制知之甚少。在本研究中，我们研究了 MLB 在 SAH 中的神经保护作用，并探讨了其潜在的机制。成年雄性 Sprague-Dawley 大鼠通过血管内穿孔过程制作 SAH 模型。SAH 后 30[Formula: see text]min 腹腔内给予 MLB，剂量为 25[Formula: see text]mg/kg 或 50[Formula: see text]mg/kg。我们发现，给予 MLB 可显著减轻 SAH 后脑水肿和神经功能缺损。此外，免疫荧光染色显示 MLB 剂量依赖性地抑制小胶质细胞的激活并减少神经元凋亡。Western blot 分析表明，MLB 降低了促炎细胞因子 TNF-[Formula: see text]和促凋亡蛋白 cleaved caspase-3 的表达。更重要的是，MLB 增加了 SIRT1 的表达，同时抑制了 NF-[Formula: see text]B 的乙酰化。此外，SAH 后预先给予 Sirtinol（SIRT1 的选择性抑制剂）可逆转 MLB 的所有上述作用。总之，我们的结果表明，MLB 通过抑制神经炎症和细胞凋亡对 SAH 发挥强大的神经保护作用。MLB 对 SAH 的神经保护作用可能是通过调节 SIRT1/NF-[Formula: see text]B 通路发挥的。MLB 或 SIRT1/NF-[Formula: see text]B 通路可能是治疗 SAH 的一种新的有前途的治疗策略。
