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: Lei Zhao, Rui An, Yang Yang, Xiangmin Yang, Haixiao Liu, Liang Yue, Xia Li, Yan Lin, Russel J Reiter, Yan Qu
• Journal: Journal of pineal research (J Pineal Res) Vol. 59 Issue 2 Pg. 230-9 (Sep 2015) ISSN: 1600-079X [Electronic] England
• PMID: 26094939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Cytokines
• Sirt1 protein, mouse
• Sirtuin 1
• Melatonin

Topics

• Animals
• Apoptosis (drug effects)
• Brain Injuries (enzymology, pathology)
• Cytokines (metabolism)
• Gene Expression Regulation (drug effects)
• Inflammation (enzymology, pathology)
• Male
• Melatonin (pharmacology)
• Mice
• Oxidative Stress (drug effects)
• Sepsis (metabolism, pathology)
• Signal Transduction (drug effects)
• Sirtuin 1 (metabolism)