Venkatramanujam Srinivasan

Melatonin - a pleiotropic, orchestrating regulator molecule

Melatonin, the neurohormone of the pineal gland, is also produced by various other tissues and cells. It acts via G protein-coupled receptors expressed in various areas of the central nervous system and in peripheral tissues. Parallel signaling mechanisms lead to cell-specific control and recruitment of downstream factors, including various kinases, transcription factors and ion channels. Additional actions via nuclear receptors and other binding sites are likely. By virtue of high receptor density in the circadian pacemaker, melatonin is involved in the phasing of circadian rhythms and sleep promotion. Additionally, it exerts effects on peripheral oscillators, including phase coupling of parallel cellular clocks based on alternate use of core oscillator proteins. Direct central and peripheral actions concern the up- or downregulation of various proteins, among which inducible and neuronal NO synthases seem to be of particular importance for antagonizing inflammation and excitotoxicity. The methoxyindole is also synthesized in several peripheral tissues, so that the total content of tissue melatonin exceeds by far the amounts in the circulation. Emerging fields in melatonin research concern receptor polymorphism in relation to various diseases, the control of sleep, the metabolic syndrome, weight control, diabetes type 2 and insulin resistance, and mitochondrial effects. Control of electron flux, prevention of bottlenecks in the respiratory chain and electron leakage contribute to the avoidance of damage by free radicals and seem to be important in neuroprotection, inflammatory diseases and, presumably, aging. Newly discovered influences on sirtuins and downstream factors indicate that melatonin has a role in mitochondrial biogenesis.

Bidirectional communication between sleep and circadian rhythms and its implications for depression: Lessons from agomelatine

Depression is a family of complex and multifactorial illnesses that are characterized by disruptions in the functioning of a number of physiological, neuroendocrine and behavioral processes. Of these, sleep disturbance and circadian rhythm abnormalities constitute the most prevalent signs of depressive illness. Difficulty in falling asleep, decreases in total sleep time and sleep efficiency, early morning awakenings, and rapid eye movement sleep alterations are all commonly seen in depressed patients. Advances or delays in the phase of circadian rhythms have been documented in patients with major depressive disorder (MDD), bipolar disorder and patients with seasonal affective disorder (SAD). The disturbances in the amplitude and rhythm of melatonin secretion that occur in patients with depression resemble those seen in subjects with chronobiological disorders. The finding that insomnia and circadian rhythm abnormalities are prominent features in depression suggests that a close link exists between melatonin secretion disturbance and depressed mood. This inference has been further strengthened by the finding that agomelatine, a recently introduced melatonergic agent with a novel mechanism of action, has beneficial effects in patients with MDD, bipolar disorder or SAD. Among agomelatines characteristics are a rapid onset of action and a pronounced effectiveness for improving sleep efficiency and correcting circadian rhythm abnormalities. Disruptions in melatonin secretion or availability may be the common factor, which underlies depressive disorder and its prominent signs and symptoms such as sleep and circadian rhythm abnormalities.

Therapeutic potential of melatonin and its analogs in Parkinson’s disease: focus on sleep and neuroprotection

Sleep disorders constitute major nonmotor features of Parkinson’s disease (PD) that have a substantial effect on patients’ quality of life and can be related to the progression of the neurodegenerative disease. They can also serve as preclinical markers for PD, as it is the case for rapid eye movement (REM)-associated sleep behavior disorder (RBD). Although the etiology of sleep disorders in PD remains undefined, the assessment of the components of the circadian system, including melatonin secretion, could give therapeutically valuable insight on their pathophysiopathology. Melatonin is a regulator of the sleep/wake cycle and also acts as an effective antioxidant and mitochondrial function protector. A reduction in the expression of melatonin MT1 and MT2 receptors has been documented in the substantia nigra of PD patients. The efficacy of melatonin for preventing neuronal cell death and for ameliorating PD symptoms has been demonstrated in animal models of PD employing neurotoxins. A small number of controlled trials indicate that melatonin is useful in treating disturbed sleep in PD, in particular RBD. Whether melatonin and the recently developed melatonergic agents (ramelteon, tasimelteon, agomelatine) have therapeutic potential in PD is also discussed.

Melatonin and human reproduction: Shedding light on the darkness hormone

Melatonin, N-acetyl-5-methoxytryptamine, is a molecule with diverse physiological functions. This neuro-hormone affects reproductive performance in a wide variety of species. In most animals, but not exclusively all, melatonin has an antigonadotrophic effect. The seasonal changes in the number of hours per day that melatonin is secreted mediate the temporal coupling of reproductive activity to seasonal changes in day-length. These observations stimulated a search for a role for the pineal gland and melatonin in human reproduction. Clinical experience related to this issue has yielded inconclusive and sometimes conflicting results. This article reviews the current available evidence concerning the effects of melatonin on human reproductive processes (e.g., puberty, ovulation, pregnancy, and fertility). Possible reasons for the vagueness and elusiveness of the clinical effects are discussed.

Jet lag, circadian rhythm sleep disturbances, and depression: the role of melatonin and its analogs

Traveling through several time zones results in a constellation of symptoms known as jet lag. These include reduced alertness, daytime fatigue, loss of appetite, reduced cognitive skills, and disruption of the sleep/wake cycle. In susceptible air travel passengers, jet lag may exacerbate affective illness and result in psychiatric morbidity. Dysregulation of circadian rhythms and melatonin secretion represent the common underlying factor in jet lag and other circadian disorders. Recent studies have established the effectiveness of strategically timed administration of melatonin and appropriate timed exposure to environmental schedules including light in counteracting the dysregulation (chronobiologic actions). With the introduction of melatonergic agonists such as ramelteon and tasimelteon, which have both a stronger affinity for MT1 and MT2 melatonin receptors and a longer half-life, new therapeutic options now exist for treating the sleep disturbances associated with jet lag. The melatonin analogs are unique inasmuch as they can also enhance daytime alertness. The recently introduced melatonergic antidepressant agomelatine, which has established its supremacy over other antidepressants in having a significant chronobiologic activity, represents a good choice for treating depressive symptoms that are associated with jet lag.

Melatonin in antinociception: its therapeutic applications.

The intensity of pain sensation exhibits marked day and night variations. Since the intensity of pain perception is low during dark hours of the night when melatonin levels are high, this hormone has been implicated as one of the prime antinociceptive substances. A number of studies have examined the antinociceptive role of melatonin in acute, inflammatory and neuropathic pain animal models. It has been demonstrated that melatonin exerts antinociceptive actions by acting at both spinal cord and supraspinal levels. The mechanism of antinociceptive actions of melatonin involves opioid, benzodiazepine, α1- and α2-adrenergic, serotonergic and cholinergic receptors. Most importantly however, the involvement of MT1/MT2 melatonergic receptors in the spinal cord has been well documented as an antinociceptive mechanism in a number of animal models of pain perception. Exogenous melatonin has been used effectively in the management of pain in medical conditions such as fibromyalgia, irritable bowel syndrome and migraine and cluster headache. Melatonin has been tried during surgical operating conditions and has been shown to enhance both preoperative and post-operative analgesia. The present review discusses the available evidence indicating that melatonin, acting through MT1/MT2 melatonin receptors, plays an important role in the pathophysiological mechanism of pain.

Melatonin, Immune Function and Cancer

Melatonin is a natural substance ubiquitous in distribution and present in almost all species ranging from unicellular organisms to humans. In mammals, melatonin is synthesized not only in the pineal gland but also in many other parts of the body, including the eyes, bone marrow, gastrointestinal tract, skin and lymphocytes. Melatonin influences almost every cell and can be traced in membrane, cytoplasmic, mitochondrial and nuclear compartments of the cell. The decline in the production of melatonin with age has been suggested as one of the major contributors to immunosenescence and development of neoplastic diseases. Melatonin is a natural antioxidant with immunoenhancing properties. T-helper cells play an important role for protection against malignancy and melatonin has been shown to enhance T-helper cell response by releasing interleukin-2, interleukin-10 and interferon-γ. Melatonin is effective in suppressing neoplastic growth in a variety of tumors like melanoma, breast and prostate cancer, and ovarian and colorectal cancer. As an adjuvant therapy, melatonin can be beneficial in treating patients suffering from breast cancer, hepatocellular carcinoma or melanoma. In this paper, a brief review of recent patents on melatonin and cancer has also been presented.

Ramelteon: a Review of its Therapeutic Potential in Sleep Disorders

Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT1 and MT2 melatonin receptors. Ramelteon’s half-life is longer than that of melatonin, being metabolized in the body to four main metabolites, M-I, M-II, M-III, and M-IV. M-II has an affinity to MT1 and MT2 of about one-tenth of the parent compound, but its concentration in the circulation exceeds that of ramelteon by more than an order of magnitude. Ramelteon is effective in decreasing latency to persistent sleep and increasing total sleep time in freely moving monkeys. A number of clinical studies have been undertaken to study the efficacy of ramelteon in subjects with chronic insomnia. In almost all of these studies, ramelteon, in various doses of 4, 8, or 16 mg most commonly, significantly reduced sleep latency and increased sleep duration. Its primary action in sleep promotion is not a generalized gamma-aminobutyric (GABA)-ergic central nervous system depression, but rather it acts as a melatonergic agonist in the suprachiasmatic nucleus (and at other central nervous system sites), from where downstream processes, including GABA-ergic effects, are controlled via the hypothalamic sleep switch. Unlike other commonly prescribed hypnotic drugs, ramelteon is not associated with next morning hangover effects or reductions in alertness, nor has it been shown to cause withdrawal symptoms. The adverse symptoms reported with ramelteon are mild. All long-term investigations that have been carried out support the conclusion that ramelteon is a well tolerated and effective drug for the treatment of insomnia.

Melatonin in Mitochondrial Dysfunction and Related Disorders

Mitochondrial dysfunction is considered one of the major causative factors in the aging process, ischemia/reperfusion (I/R), septic shock, and neurodegenerative disorders like Parkinsons disease (PD), Alzheimers disease (AD), and Huntingtons disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective for preventing oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. In addition, melatonin is known to retard aging and to inhibit the lethal effects of septic shock or I/R lesions by maintaining respiratory complex activities, electron transport chain, and ATP production in mitochondria. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants. Melatonin has thus emerged as a major potential therapeutic tool for treating neurodegenerative disorders such as PD or AD, and for preventing the lethal effects of septic shock or I/R.

Melatonin and Its Agonist Ramelteon in Alzheimer's Disease: Possible Therapeutic Value

Alzheimers disease (AD) is an age-associated neurodegenerative disease characterized by the progressive loss of cognitive function, loss of memory and insomnia, and abnormal behavioral signs and symptoms. Among the various theories that have been put forth to explain the pathophysiology of AD, the oxidative stress induced by amyloid β-protein (Aβ) deposition has received great attention. Studies undertaken on postmortem brain samples of AD patients have consistently shown extensive lipid, protein, and DNA oxidation. Presence of abnormal tau protein, mitochondrial dysfunction, and protein hyperphosphorylation all have been demonstrated in neural tissues of AD patients. Moreover, AD patients exhibit severe sleep/wake disturbances and insomnia and these are associated with more rapid cognitive decline and memory impairment. On this basis, the successful management of AD patients requires an ideal drug that besides antagonizing Aβ-induced neurotoxicity could also correct the disturbed sleep-wake rhythm and improve sleep quality. Melatonin is an effective chronobiotic agent and has significant neuroprotective properties preventing Aβ-induced neurotoxic effects in a number of animal experimental models. Since melatonin levels in AD patients are greatly reduced, melatonin replacement has the potential value to be used as a therapeutic agent for treating AD, particularly at the early phases of the disease and especially in those in whom the relevant melatonin receptors are intact. As sleep deprivation has been shown to produce oxidative damage, impaired mitochondrial function, neurodegenerative inflammation, and altered proteosomal processing with abnormal activation of enzymes, treatment of sleep disturbances may be a priority for arresting the progression of AD. In this context the newly introduced melatonin agonist ramelteon can be of much therapeutic value because of its highly selective action on melatonin MT1/MT2 receptors in promoting sleep.