title: Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress: the role of SIRT1 signaling.
abstract: 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 (30 mg/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-α, IL-1β, 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-κB, 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-α, IL-1β, 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-κB, 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.
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Radiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Rui
authors.initials: R
authors.lastname: An
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Haixiao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yue
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Scientific Research, The Fourth Military Medical University, Xi'an, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001930:Brain Injuries / Q000201:enzymology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D018805:Sepsis / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D016207:Cytokines; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D008550:Melatonin
keywords: SIRT1 signaling; cecal ligation and puncture; inflammation; melatonin; oxidative stress; septic encephalopathy