Short- and Long-Term Protective Effects of Melatonin in a Mouse Model of Sepsis-Associated Encephalopathy
Brain dysfunction is a common complication after sepsis and is an independent risk factor for a poor prognosis, which is partly attributed to the dysregulated inflammatory response and oxidative damage. Melatonin regulates the sleep–wake cycle and also has potent anti-inflammatory and antioxidant properties, yet the protective effects of melatonin on sepsis-induced neurobehavioral dysfunction remain to be elucidated. In the present study, melatonin was administered intraperitoneally daily at a dose of 10 mg/kg for three consecutive days immediately (early treatment) or 7 days (delayed treatment) after sham operation or cecal ligation and puncture (CLP), followed by an additional treatment in drinking water until the end of behavioral tests. The concentrations of pro-inflammatory cytokines (tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) were determined at the indicated time points. Compared with the CLP + vehicle group, we found that early melatonin treatment resulted in increased survival rate but not improvement in measures of neurobehavioral outcomes, which was accompanied by significantly lower plasma level of IL-1β. Intriguingly, delayed melatonin treatment improved neurobehavioral dysfunction by normalization of hippocampal BDNF and GDNF expressions. In conclusion, our study suggests the beneficial effects of both early and delayed melatonin treatment after sepsis development, which implicates melatonin has a potential therapeutic value in sepsis-associated organ damage including brain dysfunction.
KEY WORDSsepsis melatonin cognitive function neuroplasticity
This study was supported by grants from the National Science Foundation of China (Nos. 81471105, 81771156, 81772126) and Jiangsu Provincial Medical Youth Talent (QNRC2016822).
Compliance with Ethical Standards
The study protocol was approved by the Ethics Committee of the Nanjing Integrated Traditional Chinese and Western Medicine Hospital, affiliated with the Nanjing University of Chinese Medicine, and all procedures were performed in accordance with the Guideline for the Care and Use of Laboratory Animals from the National Institutes of Health, USA.
Conflict of Interest
The authors declare that they have no competing interests.
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