The multiple protective roles and molecular mechanisms of melatonin and its precursor N-acetylserotonin in targeting brain injury and liver damage and in maintaining bone health

• Published in: Free radical biology & medicine Vol. 130; pp. 215 - 233
• Main Authors: Luo, Chengliang, Yang, Qiang, Liu, Yuancai, Zhou, Shuanhu, Jiang, Jiying, Reiter, Russel J., Bhattacharya, Pallab, Cui, Yongchun, Yang, Hongwei, Ma, He, Yao, Jiemin, Lawler, Sean E., Zhang, Xinmu, Fu, Jianfang, Rozental, Renato, Aly, Hany, Johnson, Mark D., Chiocca, E. Antonio, Wang, Xin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2019
• Subjects: Animals; Bone health; Brain Injuries - drug therapy; Brain Injuries - metabolism; Brain injury; Humans; Liver damage; Liver Diseases - drug therapy; Liver Diseases - metabolism; Melatonin; Melatonin - metabolism; Melatonin receptors; N-acetylserotonin; Neuroprotective Agents - pharmacology; Osteoporosis - drug therapy; Osteoporosis - metabolism; Oxidative Stress; Receptor, Melatonin, MT1 - metabolism; Receptor, Melatonin, MT2 - metabolism; Receptors, Melatonin - metabolism; Regeneration; Serotonin - analogs & derivatives; Serotonin - metabolism; Sleep - physiology; Melatonin receptors; NAS; Oxidative stress; Melatonin; BBB; H-I; ALS; N-acetylserotonin; CNS; Liver damage; BDL; MDA; I/R; Bone health; LDH; OHSCs; SD; TBI; GSH; AIF; MCAO; AST; AD; HIE; SOD; MT2; MT1; ER; MT3; OGD; AP; ICH; PCD; PD; ROS; PI; SAH; HD; Brain injury
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2018.10.402

Melatonin is a neurohormone associated with sleep and wakefulness and is mainly produced by the pineal gland. Numerous physiological functions of melatonin have been demonstrated including anti-inflammation, suppressing neoplastic growth, circadian and endocrine rhythm regulation, and its potent antioxidant activity as well as its role in regeneration of various tissues including the nervous system, liver, bone, kidney, bladder, skin, and muscle, among others. In this review, we summarize the recent advances related to the multiple protective roles of melatonin receptor agonists, melatonin and N-acetylserotonin (NAS), in brain injury, liver damage, and bone health. Brain injury, including traumatic brain injury, ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and newborn perinatal hypoxia-ischemia encephalopathy, is a major cause of mortality and disability. Liver disease causes serious public health problems and various factors including alcohol, chemical pollutants, and drugs induce hepatic damage. Osteoporosis is the most common bone disease in humans. Due in part to an aging population, both the cost of care of fracture patients and the annual fracture rate have increased steadily. Despite the discrepancy in the pathophysiological processes of these disorders, time frames and severity, they may share several common molecular mechanisms. Oxidative stress is considered to be a critical factor in these pathogeneses. We update the current state of knowledge related to the molecular processes, mainly including anti-oxidative stress, anti-apoptosis, autophagy dysfunction, and anti-inflammation as well as other properties of melatonin and NAS. Particularly, the abilities of melatonin and NAS to directly scavenge oxygen-centered radicals and toxic reactive oxygen species, and indirectly act through antioxidant enzymes are disscussed. In this review, we summarize the similarities and differences in the protection provided by melatonin and/or NAS in brain, liver and bone damage. We analyze the involvement of melatonin receptor 1A (MT1), melatonin receptor 1B (MT2), and melatonin receptor 1C (MT3) in the protection of melatonin and/or NAS. Additionally, we evaluate their potential clinical applications. The multiple mechanisms of action and multiple organ-targeted properties of melatonin and NAS may contribute to development of promising therapies for clinical trials. [Display omitted] •Melatonin and NAS are protective agents for brain injury, liver damage and bone health.•Melatonin and NAS are anti-oxidative stress and anti-inflammation.•Melatonin and NAS are against autophagy dysfunction and anti-apoptosis.•MT1/MT2 are needed for brain and liver injuries and MT2 is important for bone health.•Melatonin and NAS will be likely to show utility in clinical trials.