Zhang Xiang-Sheng, Lu Yue, Li Wen, Tao Tao, Wang Wei-Han, Gao Sen, Zhou Yan, Guo Yi-Ting, Liu Cang, Zhuang Zong, Hang Chun-Hua, Li Wei
Department of Neurosurgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Br J Pharmacol. 2021 Sep;178(18):3648-3666. doi: 10.1111/bph.15507. Epub 2021 May 27.
Dioscin has multiple biological activities and is beneficial for cardiovascular and cerebral vascular diseases. Here, we investigated the protective effects of dioscin against subarachnoid haemorrhage and the molecular mechanisms involved.
Dioscin was administered after subarachnoid haemorrhage induced in rats. MCC950, a potent selective nod-like receptor pyrin domain-containing 3 (NLRP3) inhibitor, was used to suppress NLRP3 and EX527 (selisistat) was used to inhibit sirtuin 1 (SIRT1).
In vivo, dioscin inhibited acute inflammatory response, oxidative damage, neurological impairment and neural cell degeneration after subarachnoid haemorrhage along with dramatically suppressing NLRP3 inflammasome activation. While pretreatment with MCC950 reduced the inflammatory response and improved neurological outcomes it did not lessen ROS production. However, giving dioscin after MCC950 reduced acute brain damage and ROS production. Dioscin increased SIRT1 expression after subarachnoid haemorrhage, whereas EX527 abolished the up-regulation of SIRT1 induced by dioscin and offset the inhibitory effects of dioscin on NLRP3 inflammasome activation. EX527 pretreatment also reversed the neuroprotective effects of dioscin against subarachnoid haemorrhage. Similarly, in vitro, dioscin dose-dependently suppressed inflammatory response, oxidative damage and neuronal degeneration and improved cell viability in neurons and microglia co-culture system. These effects were associated with inhibition of the NLRP3 inflammasome and stimulation of SIRT1 signalling, which could be inhibited by EX527 pretreatment.
Dioscin provides protection against subarachnoid haemorrhage via the suppression of NLRP3 inflammasome activation through SIRT1-dependent pathway. Dioscin may be a new candidate to ameliorate early brain injury after subarachnoid haemorrhage.
薯蓣皂苷具有多种生物学活性，对心血管和脑血管疾病有益。在此，我们研究了薯蓣皂苷对蛛网膜下腔出血的保护作用及其相关分子机制。
在大鼠诱导蛛网膜下腔出血后给予薯蓣皂苷。使用强效选择性含吡咯结构域的NOD样受体3（NLRP3）抑制剂MCC950抑制NLRP3，使用EX527（西利司他）抑制沉默调节蛋白1（SIRT1）。
在体内，薯蓣皂苷可抑制蛛网膜下腔出血后的急性炎症反应、氧化损伤、神经功能障碍和神经细胞变性，同时显著抑制NLRP3炎性小体激活。虽然用MCC950预处理可降低炎症反应并改善神经功能结局，但并未减少活性氧生成。然而，在MCC950后给予薯蓣皂苷可减轻急性脑损伤和活性氧生成。蛛网膜下腔出血后薯蓣皂苷可增加SIRT1表达，而EX527消除了薯蓣皂苷诱导的SIRT1上调，并抵消了薯蓣皂苷对NLRP3炎性小体激活的抑制作用。EX527预处理也逆转了薯蓣皂苷对蛛网膜下腔出血的神经保护作用。同样，在体外，薯蓣皂苷在神经元和小胶质细胞共培养系统中剂量依赖性地抑制炎症反应、氧化损伤和神经元变性，并提高细胞活力。这些作用与抑制NLRP3炎性小体和刺激SIRT1信号传导有关，而EX527预处理可抑制这些作用。
薯蓣皂苷通过SIRT1依赖性途径抑制NLRP3炎性小体激活，从而为蛛网膜下腔出血提供保护。薯蓣皂苷可能是改善蛛网膜下腔出血后早期脑损伤的新候选药物。
