Melatonin in the oral cavity: physiological and pathological implications.

BACKGROUND AND OBJECTIVES: The purpose of this article was to summarize what is known about the function of melatonin in the oral cavity. MATERIAL AND METHODS: Databases were searched for the relevant published literature to 30 November, 2013. The following search items were used in various combinations: melatonin, gingiva, periodontium, inflammation, herpes, alveolar bone, periodontal ligament, dental implants, xerostomia, methacrylate, chlorhexidine, cancer. The literature uncovered is summarized herein. RESULTS: Salivary melatonin levels exhibit a circadian rhythm with highest values at night. Melatonin has both receptor-mediated and receptor-independent actions in cells of the oral cavity. Melatonin is released into the saliva by the acinar cells of the major salivary glands and via the gingival fluid. Functions of melatonin in the oral cavity are likely to relate primarily to its anti-inflammatory and antioxidant activities. These actions may suppress inflammation of the gingiva and periodontium, reduce alveolar bone loss, abrogate herpes lesions, enhance osteointegration of dental implants, limit oral cancer, and suppress disorders that have a free radical component. Sublingual melatonin tablets or oral melatonin sprays and topical melatonin-containing gel, if used on a regular basis, may improve overall oral health and reduce mucosal lesions. CONCLUSION: Collectively, the results indicate that endogenously-produced and exogenously-applied melatonin are beneficial to the oral cavity.

The false thyroid capsule: new findings.

PURPOSE: The false thyroid capsule is an important anatomical structure involved in thyroidectomy, yet it is rarely studied. This study aimed to define the anatomy of the false thyroid capsule, and its clinical significance. METHODS: A prospective study was performed involving 151 patients with goitre who underwent thyroid lobectomy. The anatomy of the false thyroid capsule was carefully documented intra-operatively. RESULTS: The false thyroid capsule enclosed the inferior and middle thyroid veins and the superior thyroid vessels, forming a mesentery-like structure by attaching to the gland. Once the unilateral lobe had been removed, the thyroid mesentery could be seen to have a C-shaped edge. The recurrent laryngeal nerve, inferior thyroid artery and parathyroid glands were located beneath the C-shaped edge of the thyroid mesentery. CONCLUSION: The thyroid mesentery is a distinctive structure that can be used as a guide for surgical dissection.

The photoperiod, circadian regulation and chronodisruption: the requisite interplay between the suprachiasmatic nuclei and the pineal and gut melatonin.

The current scientific literature is replete with investigations providing information on the molecular mechanisms governing the regulation of circadian rhythms by neurons in the suprachiasmatic nucleus (SCN), the master circadian generator. Virtually every function in an organism changes in a highly regular manner during every 24-hour period. These rhythms are believed to be a consequence of the SCN, via neural and humoral means, regulating the intrinsic clocks that perhaps all cells in organisms possess. These rhythms optimize the functions of cells and thereby prevent or lower the incidence of pathologies. Since these cyclic events are essential for improved cellular physiology, it is imperative that the SCN provide the peripheral cellular oscillators with the appropriate time cues. Inasmuch as the 24-hour light:dark cycle is a primary input to the central circadian clock, it is obvious that disturbances in the photoperiodic environment, e.g., light exposure at night, would cause disruption in the function of the SCN which would then pass this inappropriate information to cells in the periphery. One circadian rhythm that transfers time of day information to the organism is the melatonin cycle which is always at low levels in the blood during the day and at high levels during darkness. With light exposure at night the amount of melatonin produced is compromised and this important rhythm is disturbed. Another important source of melatonin is the gastrointestinal tract (GIT) that also influences the circulating melatonin is the generation of this hormone by the entero-endocrine (EE) cells in the gut following ingestion of tryptophan-containing meal. The consequences of the altered melatonin cycle with the chronodisruption as well as the alterations of GIT melatonin that have been linked to a variety of pathologies, including those of the gastrointestinal tract.

Drug-mediated ototoxicity and tinnitus: alleviation with melatonin.

This review evaluates the published basic science and clinical reports related to the role of melatonin in reducing the side effects of aminoglycosides and the cancer chemotherapeutic agent cisplatin, in the cochlea and vestibule of the inner ear. A thorough search of the literature was performed using available databases for the purpose of uncovering articles applicable to the current review. Cochlear function was most frequently evaluated by measuring otoacoustic emissions and their distortion products after animals were treated with cytotoxic drugs alone or in combination with melatonin. Vestibular damage due to aminoglycosides was evaluated by estimating hair cell loss in explanted utricles of newborn rats. Tinnitus was assessed in patients who received melatonin using a visual analogue scale or the Tinnitus Handicap Inventory. Compared to a mixture of antioxidants which included tocopherol, ascorbate, glutathione and N-acetyl-cysteine, melatonin, also a documented antioxidant, was estimated to be up to 150 times more effective in limiting the cochlear side effects, evaluated using otoacoustic emission distortion products, of gentamicin, tobramycin and cisplatin. In a dose-response manner, melatonin also reduced vestibular hair cell loss due to gentamicin treatment in explanted utricles of newborn rats. Finally, melatonin (3 mg daily) limited subjective tinnitus in patients. These findings suggest the potential use of melatonin to combat the ototoxicity of aminoglycosides and cancer chemotherapeutic agents. Additional studies at both the experimental and clinical levels should be performed to further document the actions of melatonin at the cochlear and vestibular levels to further clarify the protective mechanisms of action of this ubiquitously-acting molecule. Melatonin's low cost and minimal toxicity profile supports its use to protect the inner ear from drug-mediated damage.

Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity.

A worldwide increase in the incidence of obesity indicates the unsuccessful battle against this disorder. Obesity and the associated health problems urgently require effective strategies of treatment. The new discovery that a substantial amount of functional brown adipose tissue (BAT) is retained in adult humans provides a potential target for treatment of human obesity. BAT is active metabolically and disposes of extra energy via generation of heat through uncoupling oxidative phosphorylation in mitochondria. The physiology of BAT is readily regulated by melatonin, which not only increases recruitment of brown adipocytes but also elevates their metabolic activity in mammals. It is speculated that the hypertrophic effect and functional activation of BAT induced by melatonin may likely apply to the human. Thus, melatonin, a naturally occurring substance with no reported toxicity, may serve as a novel approach for treatment of obesity. Conversely, because of the availability of artificial light sources, excessive light exposure after darkness onset in modern societies should be considered a potential contributory factor to human obesity as light at night dramatically reduces endogenous melatonin production. In the current article, the potential associations of melatonin, BAT, obesity and the medical implications are discussed.

Melatonin inhibits fatty acid-induced triglyceride accumulation in ROS17/2.8 cells: implications for osteoblast differentiation and osteoporosis.

Melatonin is produced not only by the pineal gland but by cells of the bone marrow. Moreover, melatonin is known to promote osteogenic differentiation in several cell line models and in multipotential bone marrow mesenchymal stem cells. Fatty acids have been independently shown to direct such cells to acquire the phenotype and molecular characteristics of adipocytes. To examine the effect of melatonin on intracellular triglyceride accumulation, an indicator of adipogenic differentiation in the rat osteoblast-like ROS17/2.8 cell line, cells were incubated with added oleic acid (100 muM), fixed and stained with Oil Red O. Cellular lipid accumulation was quantitated by an Oil Red O method highly specific for triglycerides and expressed as a triglyceride accumulation index (TGAI, triglyceride per cell). Melatonin in nanomolar concentrations inhibited oleic acid-induced triglyceride accumulation. To identify the mechanism by which melatonin reduces triglyceride accumulation, cells were incubated with the two melatonin receptor antagonists, luzindole and S20928, or forskolin, a stimulator of adenylyl cyclase and cAMP production. These compounds prevented the inhibitory effect of melatonin on triglyceride accumulation, indicating that melatonin acts through known melatonin receptor-mediated mechanisms. In view of the previously demonstrated positive effects of melatonin in promoting osteoblastic differentiation in ROS17/2.8 cells and their reciprocal adipocytic differentiation induced by fatty acids, our observations may serve to relate the known age-related decreases of melatonin production, the shift in the bone marrow toward an adipocytic line of cell development, and the development of osteoporosis during aging.

Melatonin defeats neurally-derived free radicals and reduces the associated neuromorphological and neurobehavioral damage.

Melatonin and its metabolites are potent antioxidants by virtue of their ability to scavenge both oxygen-based and nitrogen-based radicals and intermediates but also as a consequence of their ability to stimulate the activity of antioxidative enzymes. Melatonin also prevents electron leakage from the mitochondrial electron transport chain thereby diminishing free radical generation; this process is referred to as radical avoidance. The fact that melatonin and its metabolites are all efficient radical scavengers indicates that melatonin is a precursor molecule for a variety of intracellular reducing agents. In specific reference to the brain, melatonin also has an advantage over some other antioxidants given that it readily passes through the blood-brain-barrier. This, coupled with the fact that it and its by-products are particularly efficient detoxifiers of reactive species, make these molecules of major importance in protecting the brain from oxidative/nitrosative abuse. This review summarizes the literature on two brain-related situations, i.e., traumatic brain and spinal cord injury and ischemia/reperfusion, and the neurodegenerative disease, amyotrophic lateral sclerosis, where melatonin has been shown to have efficacy in abating neural damage. These, however, are not the only age-associated neurodegenerative states where melatonin has been found to be protective.

The chemistry of melatonin's interaction with reactive species.

Melatonin has been shown to be an effective antioxidant in a number of experimental models both in vitro and in vivo. Considering the data available, it is now clear that the indoleamine is involved in antioxidative mechanisms more complex than originally envisaged. These range from the direct radical scavenging of a variety of radicals and reactive species to the control and/or modulation of a number of processes which may trigger a redox imbalance between antioxidant and prooxidant species. This review focuses on the direct radical scavenging activity of melatonin and provides a summary of the mechanisms of the reactions between the indoleamine and reactive species in pure chemical solutions. These actions likely account for at least some of the protective actions of melatonin under conditions of high oxidative stress.

Neurally-mediated and neurally-independent beneficial actions of melatonin in the gastrointestinal tract.

Melatonin (N-acetyl-5-methoxytryptamine), originally discovered in the pineal gland, is now known also to be present in the gastrointestinal tract from the stomach to the colon. It is localized and likely synthesized in the enterochromaffin cells of the mucosal lining. Its functions in the gut generally seem to be protective of the mucosa from erosion and ulcer formation and to possibly influence movement of the gastrointestinal contents through the digestive system. In this brief review, we summarize the work documenting the function of melatonin in influencing bicarbonate secretion in the stomach and its role in preventing and repairing ulcers in the stomach and duodenum. Melatonin's actions in the control of bicarbonate secretion involve the central and peripheral sympathetic nervous systems and the actions are receptor mediated. Conversely, melatonin's actions in reducing ulcer formation also seemingly involve the ability of the indole to directly scavenge toxic oxygen-based reactants, e.g., the hydroxyl radical, and possibly to promote antioxidative enzyme activities. These same processes may be involved in the mechanisms by which melatonin promotes ulcer healing. Additionally, however, melatonin's effects on the healing of ulcers includes actions of blood flow in the margins of the ulcer and also on the sensory nerves. All indications are that melatonin has a variety of beneficial effects in the gastrointestinal tract. It is likely, however, that additional actions of melatonin on the digestive system will be uncovered.

Melatonin prevents oxidative damage to protein and lipid induced by ascorbate-Fe(3+)-EDTA: Comparison with glutathione and alpha-tocopherol.

OBJECTIVES: The ability of melatonin to protect protein and lipid against oxidative damage induced by an ascorbate-Fe(3+)-EDTA (AFE) system which generates the hydroxyl radical was investigated using bovine serum albumin (BSA) and phosphatidylcholine (PC) liposomes, respectively, and compared with the protective effects of reduced glutathione and alpha-tocopherol. The comparison study was also performed using PC liposomes containing BSA. METHODS: BSA, PC liposomes or their mixtures were exposed to the HO.-generating system of AFE composed of 0.1 mM EDTA-Fe(3+) and 0.5 mM ascorbate in 0.1 M phosphate buffer, pH 7.4, at 37 degrees C for 1 h. Oxidative damage of BSA was determined by measuring the carbonyl content and the fragmentation of protein by the reaction with dinitrophenylhydrazine (DNPH) and electrophoresis, respectively. Lipid peroxidation of PC liposomes was indicated by the quantity of malondialdehyde and 4hydroxyalkenals. RESULTS: Melatonin inhibited protein damage as indicated by the reduced formation of carbonyl groups and fragmentation of BSA by AFE as effectively as did glutathione while alpha-tocopherol was ineffective. Melatonin also prevented lipid peroxidation to the same extent as did alpha-tocopherol in PC liposomes. CONCLUSION: Both BSA and PC lipid exposed to AFE are effectively protected by melatonin while hydrophilic glutathione and hydrophobic alpha-tocopherol are as effective as melatonin only in one target, i.e., BSA or PC lipid, respectively.