TY  - JOUR
PY  - 2019//
TI  - Melatonin receptor activation provides cerebral protection after traumatic brain injury by mitigating oxidative stress and inflammation via the Nrf2 signaling pathway
JO  - Free radical biology and medicine
A1  - Wang, Junmin
A1  - Jiang, Chao
A1  - Zhang, Kun
A1  - Lan, Xi
A1  - Chen, Xuemei
A1  - Zang, Weidong
A1  - Wang, Zhongyu
A1  - Guan, Fangxia
A1  - Zhu, Changlian
A1  - Yang, Xiuli
A1  - Lu, Hong
A1  - Wang, Jian
SP  - 345
EP  - 355
VL  - 131
IS  - 
N2  - 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 (10mg/kg) daily at 10:00 am 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.<br><br>Copyright © 2018. Published by Elsevier Inc.<p />  <p>Language: en</p>
LA  - en
SN  - 0891-5849
UR  - http://dx.doi.org/10.1016/j.freeradbiomed.2018.12.014
ID  - ref1
ER  -