Melatonin Attenuates Thrombin-induced Inflammation in BV2 Cells and Then Protects HT22 Cells from Apoptosis
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ORIGINAL ARTICLE
Melatonin Attenuates Thrombin-induced Inflammation in BV2 Cells and Then Protects HT22 Cells from Apoptosis Jiao Tang,1 Rui Chen,2 Lingling Wang,3 Lu Yu,4 Dandan Zuo,4 Guiyun Cui ,4,5 and Xiaoqian Gong1,5
Abstract— Increasing evidence has revealed that the uncontrolled thrombin-induced inflam-
mation following intracerebral hemorrhage (ICH) plays a key role in ICH. Oxidative stress and neuroinflammatory responses are interdependent and bidirectional events. Melatonin is now recognized as an antioxidant and a free radical scavenger due to its roles in various physiological and pathological processes. The aim of this study was to explore the molecular mechanisms underlying the effects of melatonin on thrombin-induced microglial inflammation and its indirect protection of HT22 cells from p53-associated apoptosis. Melatonin treatment attenuated the expression of IL-1β, IL-18, cleaved caspase-1, and NLRP3 and decreased the production of reactive oxygen species (ROS), revealing its inhibitory effects against ROS-NLRP3 inflammasome activation. In further experiments investigating the protection conferred by melatonin, incubating HT22 cells with conditioned medium (CM) from thrombin-stimulated microglia induced HT22 cell apoptosis, and this effect was reversed after treating CM with either melatonin or N-acetyl-L-cysteine (NAC). Additionally, the Bax/Bcl-2 ratio and the levels of cleaved caspase-3 and p53 were markedly lower in the cells cultured in thrombin + melatonin-CM than in the cells cultured in thrombin-CM. Furthermore, the levels of MMP, ROS, SOD, MDA, and GSH-PX in bystander HT22 cells suggested that melatonin decreased HT22 cell apoptosis instigated via the p53-associated apoptotic pathway. Therefore, these findings strongly indicate the anti-inflammatory properties of melatonin that may suppress ROS-NLRP3 inflammasome activation and protect HT22 Jiao Tang and Rui Chen are co-first author 1
Department of Neurology, Yan Cheng City No.1 People’s Hospital, Yancheng, Jiangsu Province, China 2 Department of Neurology, The Second People’s Hospital of Huai’an and The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu Province, China 3 Department of Hematology, Yan Cheng City No.1 People’s Hospital, Yancheng, Jiangsu Province, China 4 Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China 5 To whom correspondence should be addressed to Guiyun Cui at Department of Neurology, The Affiliated Hospital of Xuzhou Medical U n i v e r s i t y, X u z h o u , J i a n g s u P r o v i n c e , C h i n a . E - m a i l : [email protected]; and ; [email protected]
0360-3997/20/0000-0001/0 # 2020 Springer Science+Business Media, LLC, part of Springer Nature
Tang, Chen, Wang, Yu, Zuo, Cui, and Gong cells against apoptosis by inhibiting the ROS-mediated p53-dependent mitochondrial apoptotic pathway. KEY WORDS: melatonin; thrombin; intracerebral hemorrhage; NLRP3; ROS; p53.
INTRODUCTION Intracerebral hemorrhage (ICH) is a life-threateni
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