Melatonin: functions and ligands

Highlights

• Pathways controlling melatonin secretion are complex.

• There are various causes of melatonin disturbance.

• Evaluation of melatonin secretion clinically requires long time treatment.

• Beneficial effect, at low dosages only, at high dosage results are diverse.

• Melatonin mediates function through, antioxidant action in most of disorders.

Melatonin is a chronobiotic substance that acts as synchronizer by stabilizing bodily rhythms. Its synthesis occurs in various locations throughout the body, including the pineal gland, skin, lymphocytes and gastrointestinal tract (GIT). Its synthesis and secretion is controlled by light and dark conditions, whereby light decreases and darkness increases its production. Thus, melatonin is also known as the ‘hormone of darkness’. Melatonin and analogs that bind to the melatonin receptors are important because of their role in the management of depression, insomnia, epilepsy, Alzheimer's disease (AD), diabetes, obesity, alopecia, migraine, cancer, and immune and cardiac disorders. In this review, we discuss the mechanism of action of melatonin in these disorders, which could aid in the design of novel melatonin receptor ligands.

Introduction

Circulating melatonin (5-methoxy-N-acetyltryptamine) in mammals is largely derived from the pineal gland 1, 2, although other organs producing melatonin include the GIT, epithelial hair follicles, skin, retina, salivary glands, platelets, lymphocytes and developing brain 3, 4. It performs a clock and calendar function in body. Along with antioxidant actions, melatonin is a biological modulator of mood, sleep, sexual behavior and circadian rhythm. Low levels of melatonin have been shown in Parkinson's disease (PD), AD, insomnia, epilepsy, ischemic injury and neuropsychiatric disorders; in addition, roles for melatonin in the development of cataracts, aging and retinitis have also been reported 5, 6.

Melatonin is a derivative of tryptophan and was discovered by Aron B. Lerner in 1958 [7]. It is synthesized mainly in the pineal gland by parenchymatous cells in response to light information received through retinohypothalamic pathways. Further light information reaches the suprachiasmatic nucleus (SCN) where the circadian clock exists. This enables the synchronization of the phases of the circadian clock with the light–dark cycle. Information relating to time passes from the SCN to the superior cervical ganglion and finally to the pineal gland. This pathway is stimulated during the night and the activity of the superior cervical region is inhibited by light stimulation. Noradrenaline is secreted by nerve terminals from the superior cervical region and activates β receptors on the pineal gland. As a result, synthesis of cAMP increases, which enhances the activity of either aralkylamine N-acetyltransferase (AANAT) or serotonin N-acetyltransferase (SNAT), rate-limiting enzymes in melatonin synthesis. These enzymes convert serotonin into N-acetyl serotonin, which with the additional help of hydroxyindole-O-methyl transferase (HIOMT), also known as acetyl serotonin N-methyltransferase (ASMT), is converted to melatonin (Fig. 1) 8, 9.

Melatonin is metabolized mainly in liver via hydroxylation at the sixth position by cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) and cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1). After hydroxylation, melatonin is excreted as a sulfate conjugate, although glucuronide conjugation can occur. Melatonin is deacetylated in the pineal gland and retina by melatonin deacetylase. In other cells, it can be metabolized by free radicals and is converted to cyclic 3- and 6-hydroxymelatonin [10]. N¹-Acetyl-N²-formyl-5-methoxykinuramine (AFMK) and N¹-acetyl-5-methoxykinuramine (AMK) are two important melatonin metabolites that have excellent radical scavenging activity. AMK is predicted to be better than melatonin in scavenging hydroxyl radicals and their scavenging efficiency depends on the radical with which they are reacting (Fig. 2) 11, 12.