Abstract
After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine. Melatonin, a hormone secreted from the pineal gland at night, plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation. Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic, locomotor activity-regulating, neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reducing, retinal, vascular, anti-tumor and antioxidant effects. It is related with memory, ovarian physiology, and osteoblast differentiation. Pathologies associated with an increase or decrease in melatonin levels are summarized in the review. Melatonin affects by four mechanisms: 1) Binding to melatonin receptors in plasma membrane, 2) Binding to intracellular proteins such as calmoduline, 3) Binding to Orphan nuclear receptors, and 4) Antioxidant effect. Receptors associated with melatonin are as follows: 1) Melatonin receptor type 1a: MT1 (on cell membrane), 2) Melatonin receptor type 1b: MT2 (on cell membrane), 3) Melatonin receptor type 1c (found in fish, amphibians and birds), 4) Quinone reductase 2 enzyme (MT3 receptor, a detoxification enzyme), 5) RZR/RORα: Retinoid-related Orphan nuclear hormone receptor (with this receptor, melatonin binds to the transcription factors in nucleus), and 6) GPR50: X-linked Melatonin-related Orphan receptor (it is effective in binding of melatonin to MT1). Melatonin agonists such as ramelteon, agomelatine, circadin, TIK-301 and tasimelteon are introduced and side effects will be discussed. In conclusion, melatonin and related drugs is a new and promising era for medicine. Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future.
Highlights
After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine
Melatonin and Associated Pathologies Melatonin is a hormone secreted from the pineal gland at night
The increase in melatonin receptor-related cyclic AMP (cAMP) in the mesolimbic dopaminergic system shows that the effect of melatonin may be present in regulation of addictive behavior [1]
Summary
Intracellular synthesis of melatonin in the pinealocyte and its effects are summarized. This enzyme belongs to the reductase group, which are involved in prevention from oxidative stress by inhibiting the electron transfer reactions of quinones [1] This enzyme (or MT3 receptor) is located in liver, kidney, heart, lung, intestine, muscle and brown fat tissue. 2) Agomelatine (Valdoxan©, Servier, France; S20098): In November 2008, it received approval from EMA (European Medicines Agency) in Europe for treatment of major depression in adults [2, 24, 44] It is a non-selective (MT1/MT2) melatonin receptor agonist + serotonergic 5-HT2c antagonist. It is the first reported melatonergic drug having anxiolytic and antidepressant effects [1]. In major depression, it is used with a daily dose of 25 mg. S29434: The most potent QR2 inhibitor as well as the most potent ligand at MT3 [54]
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