Xiang-Sheng Zhang1,2, Yue Lu2, Wen Li3, Tao Tao4, Wei-Han Wang1, Sen Gao2, Yan Zhou2, Yi-Ting Guo1, Cang Liu1, Zong Zhuang2, Chun-Hua Hang2, Wei Li2. 1. Department of Neurosurgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. 2. Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China. 3. Department of Pharmacy, Beijing Boai Hospital, China Rehabilitation Research Center, Capital Medical University, Beijing, 100068, China. 4. Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China.
Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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). KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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. This article is protected by copyright. All rights reserved.
BACKGROUND AND PURPOSE: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. EXPERIMENTAL APPROACH: 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). KEY RESULTS: 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, dioscinreduced acute brain damage, as well as the ROS production in the SAHrats 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. CONCLUSION AND IMPLICATIONS: 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. This article is protected by copyright. All rights reserved.