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Antiepileptic Antiosteoporotic Antioxidant Cardiovascular disease Circardian rhythm Hypnotic Immunodulatory Melatonin a b s t r a c t Melatonin is one of the most versatile and ubiquitous molecule widely distributed in nature has been reported to play a role in a wide variety of physiological responses including reproduction, circadian homeostasis, sleep, retinal neuromodulation, and vasomotor responses. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light ⁄ dark cycle via the suprachiasmatic nucleus. Melatonin is synthesized in all areas of the body such as gastrointestinal tract, skin, bone marrow, retina and in lymphocytes, from which it may influence other physiological functions through paracrine signalling. In addition to regulation of circadian rhythm of melatonin a variety of other physiological effects such as hypnotic, antidepressant, antiepileptic, oncostatic, immunomodulatory, antiosteoporotic, in cardiovascular disease, neuromodulatory and cerebral ischaemic condition have been reported.Moreover there is scarcity of literature that reviewed the scientific evidence for its use in these conditions. Therefore in this article we review recent advances in this research field, which is preceded by a concise account of general information about melatonin, melatonin receptors and intracellular signalling pathways for melatonin actions.

Plant and phytochemical products continue to play an important role in medicine. In this study, the toxicological potentials of the aqueous leaf extract of Catharanthus roseus G. Don 1838 in rabbits were determined. The rabbits were placed in three groups with four rabbits in each group. The control group, a second group administered with 100mg/Kg and third group administer with 360mg/Kg body weight, were tag as Group 1, 2 and 3 respectively. Increased levels of serum alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) were found to follow the treatment of rabbits with ACR suggesting liver damage. This was confirmed by the histopathological studies that reveal centrieolobular hemorrhagic necrosis of the liver. Also, there was oxidative glomerulonephritis that set in. The effect of the extract in the activity of the hepatocellular enzymes (ALT, AST, and ALP) was found to be concentration dependent. This suggest that the infusion of the leaves could cause hepatocellular damage and kidney impairment.

Melatonin is a pineal neurohormone whose secretion is influenced by circadian changes of 24 hour night and day cycle. Over the recent past, several studies have highlighted the ubiquitous influence of the circadian timing in almost all the physiologic functions. An altered/ deficient sleep-wake cycle has been correlated with physiological imbalances which are linked to the development of various disorders, viz depression, anxiety, psychosis, attention deficits, sleep deprivation and others. Melatonin and its oxidation products, viz cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykinuramine and N1-acetyl-5methoxykinuramine possess excellent antioxidant properties. Melatonin's beneficial neuroprotective properties are mostly attributed to excellent free radical scavenging properties. A gathering body of evidence has shown that besides strong antioxidant activities, melatonin is a pleiotropic regulator molecule which orchestrates multiple functions through all the three melatonin receptors, i.e. MT1, MT2, and MT3. For example, MT2 receptor agonistic activity is attributed to neuroprotective, hypnotic and anxiolytic properties while MT1 and MT2 agonistic activity is associated with the clinical efficacy of agomelatine. The third melatonin receptor has been identified as quinone reductase (QR) 2, an enzyme involved in detoxification. MT3 agonist has been linked to strong hypotensive effects in preclinical study.In conclusion, the gathering body of evidence both from preclinical and clinical literatures suggests strong antioxidant activities and diverse pleiotropic mechanisms of melatonin for potential neuroprotective role in diverse neuropsychiatric disorders. However, there is still a lack of melatonergic ligands with high selectivity and specificity to precisely target any particular neuropsychiatric disorders for which limited therapeutic options are currently available clinically.