Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress: the role of SIRT1 signaling
Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress: the role of SIRT1 signaling
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DOI：
10.1111/jpi.12254
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发表时间：
2015-09-01
影响因子：
10.3
通讯作者：
Qu, Yan
中科院分区：
文献类型：
--
作者：
Zhao, Lei;An, Rui;Qu, Yan
败血症是对感染的一种全身性炎症反应，会导致严重的神经系统并发症。先前的研究表明，褪黑素在脓毒症期间具有保护作用。此外，沉默信息调节因子1(SIRT1)被报道在脓毒症中是有益的。然而，SIRT1信号在褪黑素对败血症脑病的保护作用中的作用尚不清楚。本研究旨在探讨SIRT1在褪黑素保护作用中的作用。用SIRT1抑制剂EX527揭示SIRT1在褪黑素作用中的作用。雄性C57BL/6J小鼠行盲肠结扎穿刺术或假手术。褪黑激素(30 mg/kg)腹腔注射。记录假手术或CLP术后7d内小鼠的存活率。检测血脑屏障(BBB)完整性、脑含水量、炎性细胞因子(TNF-、IL-1、HMGB1)水平、氧化应激(超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、丙二醛(MDA))水平及细胞凋亡情况。免疫印迹法检测SIRT1、Ac-FoxO1、Ac-P53、Ac-NF-B、Bcl2、Bax的表达。结果提示，褪黑素可提高存活率，减轻脑水肿和神经细胞凋亡，保护血脑屏障的完整性。褪黑素可减少肿瘤坏死因子-1、白介素1和HMGB1的产生。褪黑素可提高超氧化物歧化酶和过氧化氢酶的活性，减少丙二醛的产生。此外，褪黑素还上调SIRT1和Bcl2的表达，下调Ac-FoxO1、Ac-P53、Ac-NF-B和Bax的表达。然而，褪黑素的保护作用被EX527取消。综上所述，我们的结果表明褪黑素通过激活SIRT1信号通路减轻脓毒症所致的脑损伤。
Sepsis is a systemic inflammatory response to infection that causes severe neurological complications. Previous studies have suggested that melatonin is protective during sepsis. Additionally, silent information regulator 1 (SIRT1) was reported to be beneficial in sepsis. However, the role of SIRT1 signaling in the protective effect of melatonin against septic encephalopathy remains unclear. This study aimed to investigate the role of SIRT1 in the protective effect of melatonin. EX527, a SIRT1 inhibitor, was used to reveal the role of SIRT1 in melatonin's action. Cecal ligation and puncture or sham operation was performed in male C57BL/6J mice. Melatonin was administrated intraperitoneally (30mg/kg). The survival rate of mice was recorded for the 7-day period following the sham or CLP operation. The blood-brain barrier (BBB) integrity, brain water content, levels of inflammatory cytokines (TNF-, IL-1, and HMGB1), and the level of oxidative stress (superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA)) and apoptosis were assessed. The expression of SIRT1, Ac-FoxO1, Ac-p53, Ac-NF-B, Bcl-2, and Bax was detected by Western blot. The results suggested that melatonin improved survival rate, attenuated brain edema and neuronal apoptosis, and preserved BBB integrity. Melatonin decreased the production of TNF-, IL-1, and HMGB1. Melatonin increased the activity of SOD and CAT and decreased the MDA production. Additionally, melatonin upregulated the expression of SIRT1 and Bcl-2 and downregulated the expression of Ac-FoxO1, Ac-p53, Ac-NF-B, and Bax. However, the protective effects of melatonin were abolished by EX527. In conclusion, our results demonstrate that melatonin attenuates sepsis-induced brain injury via SIRT1 signaling activation.