Cerebroprotection by dioscin after experimental subarachnoid hemorrhage via inhibiting NLRP3 inflammasome through SIRT1-dependent pathway.

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Dioscin possesses multiple biologic activities and is beneficial for cardiovascular and cerebral vascular diseases. Here we investigated the protective effects of dioscin against subarachnoid hemorrhage (SAH) and the involvement of underlying molecular mechanisms.Dioscin was administered after SAH. MCC950, a potent selective nod-like receptor pyrin domain-containing 3 (NLRP3) inhibitor, was used to suppress NLRP3. EX527 was adopted to inhibit sirtuin 1 (SIRT1).In vivo, dioscin markedly inhibited acute inflammatory response, oxidative damage, neurological impairment, and neural cell degeneration after SAH. Meanwhile, dioscin dramatically suppressed NLRP3 inflammasome activation. Additionally, pretreatment with MCC950 ameliorated inflammatory response and improved neurological outcomes but did not mitigate reactive oxygen species (ROS) production after SAH. In contrast, dioscin reduced acute brain damage, as well as the ROS production in the SAH rats with MCC950 pretreatment. Moreover, dioscin increased SIRT1 expression after SAH, whereas EX527 abolished the upregulation 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 SAH. 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 signaling, which could be reversed by EX527 pretreatment.Dioscin provides protection against SAH via the suppression of NLRP3 inflammasome activation through SIRT1-dependent pathway. Dioscin may be a new candidate to ameliorate EBI after SAH.

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Authors: Xiang-Sheng Zhang, Yue Lu, Wen Li, Tao Tao, Wei-Han Wang, Sen Gao, Yan Zhou, Yi-Ting Guo, Cang Liu, Zong Zhuang, Chun-Hua Hang, Wei Li