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Free Radic Biol Med. 2019 Feb 1;131:345-355. doi: 10.1016/j.freeradbiomed.2018.12.014. Epub 2018 Dec 13.

Melatonin receptor activation provides cerebral protection after traumatic brain injury by mitigating oxidative stress and inflammation via the Nrf2 signaling pathway.

Author information

1
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; Department of Anatomy, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450000, China; The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: wangjunmin@zzu.edu.cn.
2
Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
3
School of Life Science, Zhengzhou University, Zhengzhou, Henan 450000, China.
4
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Department of Anatomy, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450000, China.
6
Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China.
7
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; School of Life Science, Zhengzhou University, Zhengzhou, Henan 450000, China.
8
The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan 450052, China; Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg 40530, Sweden.
9
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
10
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China. Electronic address: zzu_luhong@163.com.
11
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jwang79@jhmi.edu.

Abstract

Traumatic brain injury (TBI) is a principal cause of death and disability worldwide. Melatonin, a hormone made by the pineal gland, is known to have anti-inflammatory and antioxidant properties. In this study, using a weight-drop model of TBI, we investigated the protective effects of ramelteon, a melatonin MT1/MT2 receptor agonist, and its underlying mechanisms of action. Administration of ramelteon (10 mg/kg) daily at 10:00 a.m. alleviated TBI-induced early brain damage on day 3 and long-term neurobehavioral deficits on day 28 in C57BL/6 mice. Ramelteon also increased the protein levels of interleukin (IL)-10, IL-4, superoxide dismutase (SOD), glutathione, and glutathione peroxidase and reduced the protein levels of IL-1β, tumor necrosis factor, and malondialdehyde in brain tissue and serum on days 1, 3, and 7 post-TBI. Similarly, ramelteon attenuated microglial and astrocyte activation in the perilesional cortex on day 3. Furthermore, ramelteon decreased Keap 1 expression, promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation, and increased levels of downstream proteins, including SOD-1, heme oxygenase-1, and NQO1 on day 3 post-TBI. However, in Nrf2 knockout mice with TBI, ramelteon did not decrease the lesion volume, neuronal degeneration, or myelin loss on day 3; nor did it mitigate depression-like behavior or most motor behavior deficits on day 28. Thus, timed ramelteon treatment appears to prevent inflammation and oxidative stress via the Nrf2-antioxidant response element pathway and might represent a potential chronotherapeutic strategy for treating TBI.

KEYWORDS:

Chronotherapy; Inflammation; NF-E2-related factor; Oxidative stress; Ramelteon; Traumatic brain injury

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