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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 28  |  Issue : 2  |  Page : 160-166

Chemical of darkness (Melatonin): A ray of glow to dentistry


1 Community Health Center, Kukanoor, Karnataka, India
2 Department of Oral Medicine and Radiology, SIBAR Institute of Dental Sciences, Guntur, Andhra Pradesh, India

Date of Submission14-Mar-2015
Date of Acceptance15-Nov-2016
Date of Web Publication02-Dec-2016

Correspondence Address:
Dr. Vijayakumar Ambaldhage
Dental Health Officer, Community Health Center, Kukanoor, Koppal (Dist), Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-1363.195131

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   Abstract 

Melatonin (MLT) is a neuroendocrine hormone secreted mainly by the pineal gland. Recent studies have shown that it is also synthesized in various other parts of the body including salivary glands. The most significant effects of MLT are because of its potent antioxidant, antiageing, immunomodulatory, shielding and antineoplastic properties. Because of these effects, it might be used therapeutically in dentistry for the potentially malignant disorders, lesions of mechanical, bacterial, fungal or viral origin. It stimulates synthesis of collagen fibers and bone formation, and can be used in postsurgical wounds caused by tooth extractions, periodontal therapies, and dental implants. Thus, it is important for the dental clinicians to be familiar with the possible therapeutic uses of MLT in dentistry. The aim of the present article is to review related articles in the literature that have focused on MLT and its applications in dentistry and to provide a quick sketch of applications of MLT in dentistry for dental clinicians. Our review concludes that the research to date certainly offers valid applications of MLT in dentistry. Meanwhile, practical strategies with the highest success rates are needed for further interventions.

Keywords: Melatonin, osteointegration, periodontal disease, pineal gland


How to cite this article:
Ambaldhage V, Naik PN, Alaparthi RK, Yelamanchili S. Chemical of darkness (Melatonin): A ray of glow to dentistry. J Indian Acad Oral Med Radiol 2016;28:160-6

How to cite this URL:
Ambaldhage V, Naik PN, Alaparthi RK, Yelamanchili S. Chemical of darkness (Melatonin): A ray of glow to dentistry. J Indian Acad Oral Med Radiol [serial online] 2016 [cited 2021 Apr 13];28:160-6. Available from: https://www.jiaomr.in/text.asp?2016/28/2/160/195131


   Introduction Top


Melatonin (MLT) is a neuroendocrine hormone secreted mainly by the pineal gland. The most significant effects of MLT are because of its potent antioxidant and antineoplastic properties. Thus, it is important for dental clinicians to be familiar with the possible therapeutic uses of MLT for oral and perioral disorders. With the aim to review related articles on applications of MLT in dentistry, a detailed literature search was performed to identify systematic reviews and research articles, using PubMed and the Cochrane Database of Systematic Reviews. Language was restricted to English. Key search terms were melatonin in saliva, gingival crevicular fluid, odontogenesis, periodontal health, osteointegration, anti-inflammation, antineoplastic and oral mucositis. All of the current authors independently extracted data for analysis and review. Two independent reviewers screened the titles and abstracts of all the articles for eligibility. When the reviewers noted that an abstract or title of an article indicated that the article was potentially useful, full copies were retrieved. Ultimately, 32 articles underwent full-text review.

MLT was first discovered in connection to the mechanism by which some amphibians and reptiles change the color of their skin. In 1917, Carey and Floyd observed that, after feeding the extract of the pineal glands of cows, the tadpole skin became light in color due to contraction of epidermal melanophores. In 1958, dermatology professor Aaron et al. at Yale University isolated the hormone from bovine pineal gland extracts and named it MLT. MLT derives its name from serotonin based on its ability to blanch the skin of amphibians. In the mid-seventies, Lynch et al. demonstrated that the production of MLT exhibits a circadian rhythm in human pineal glands. [1]

MLT (N-acetyl-5-methoxytryptamine) is a methoxyindole which is synthesized within the pinealocytes. It is a powerful hormone derived from an essential amino acid tryptophan. The master circadian clock, located in the suprachiasmatic nuclei (SCN) in the hypothalamus, controls the secretion of MLT from the pineal gland. Recent studies have shown that it is also produced extraperitoneally including retina, ovary, placenta, kidneys, respiratory tract, gastrointestinal tract (GIT) and salivary glands. [2] It is produced with a circadian rhythm characterized by elevated blood levels in the night, and hence it is known as the "chemical expression of darkness." Endogenous MLT secretion is suppressed by light according to a dose response curve such that melatonin can even be suppressed by ordinary indoor light. [2]


   Biosynthesis and Secretion Top


MLT is produced by pinealocytes through a sequence of enzymatic reactions [Figure 1]. This process requires polysynaptic activation of ß adrenergic receptors, which are indirectly regulated by neural stimulus from the SCN. Information on light/dark environments is transmitted by the retina of the eye via retinohypothalamic tract to the SCN. A neural signal is transferred to the upper thoracic cord and superior cervical ganglia, which conveys postganglionic sympathetic fibers (secretory fibers) to the pineal gland. MLT once formed is not stored in the pineal gland but is released into the blood or cerebrospinal fluid. [3]
Figure 1: Various enzymatic reactions in the melatonin synthesis

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Extraperitoneal synthesis

It is produced in several organs and MLT-forming enzymes are also found in many tissues. Its production in the retina of eye is well documented, and there is evidence of its synthesis in the lens of eye, ovary, placenta, kidney, respiratory tract, enteroendocrine cells of GIT, salivary glands and cells of the immune system. [4]

Melatonin in saliva

Approximately 70% of MLT is usually bound to albumin in the blood. Thus, the salivary MLT is believed to be from the free MLT (unbound) component in the systemic circulation that passively enters the mucous/serous cells of the major salivary glands (parotid, submaxillary, and sublingual glands). It is discharged from the acinar cells of the salivary glands due to the contraction of the myoepithelial cells. [4] The proportion of plasma MLT entering the mouth via the salivary glands appears to be relatively stable and ranges from 24 to 33%. Because only the unbound MLT in plasma enters the saliva, salivary melatonin levels reflect the proportion of free-circulating melatonin. The salivary MLT level range from 1 to 5 pg/mL in the day and up to 50 pg/mL at night. [5] Few studies have demonstrated that the salivary glands may synthesize MLT. Recently, a study by Shimozuma et al. found the expression of the enzymes that mediate the serotonin-to-MLT transformation by immunohistochemistry in the major salivary glands of the rat and in the human submandibular glands. Whether the minor salivary glands contribute to MLT concentration in the oral cavity is unknown. [6]

Melatonin in gingival crevicular fluid

Many studies have demonstrated the presence of MLT in the gingival crevicular fluid (GCF) of humans. A study by Srinath et al. compared the GCF MLT levels in healthy, gingivitis and periodontitis patients. The measured levels GCF from individuals with a healthy mouth (absence of gingivitis) was 1.54 pg/mL compared to 2.17 pg/mL in salivary fluid. The salivary and GCF MLT levels were reduced to the lowest concentrations in patients with chronic periodontitis (salivary melatonin: 0.07 pg/mL; GCF melatonin: 0.06 pg/mL). [7] Similar results were reported by Golpasand et al., [8] and Cutando et al. [9] All these studies concluded that severe inflammatory responses are associated with massive free radical generation and increased oxidative stress, which in turn leads to tissue damage and bone loss. Thus, the actions of MLT as an anti-inflammatory and antioxidative agent could be beneficial to abate the severity of inflammation and for improving the periodontal health.

Exogenous melatonin

MLT has been reported in foods including cherries (0.17-13.46 ng/g), bananas, grapes, tomato, cucumber, rice, cereals, herbs, olive oil, tea, wine and beer. Apart from natural sources, it is also available as a synthetic product in the form of sublingual tablets or oral sprays and topical gel. At a therapeutic level of 0.5-5 mg, MLT is used for the management of sleep disorders and jet lag, and for the resynchronization of circadian rhythms in situations such as blindness and shift work. Because of its sedative effect, it is also used as anxiolytic, analgesic, antihypertensive, anti-inflammatory, and antidepressant. [10]

Physiologic melatonin levels

Normal plasma MLT levels range between 14 and 60 pg/mL. MLT has its highest levels in plasma during nighttime and early mornings (60-200 pg/mL) peaking between 12 AM and 4 AM and is lowest during the day (between 12 PM and 2 PM). [7] Mean endogenous MLT production rates have been calculated to be approximately 30 µg per day. [5],[7] The salivary MLT widely varies between 1.5 and 3.5 pg/mL because it depends on various factors that control the functioning of salivary glands. The presence of melatonin in the GCF of humans was reported by Srinath et al.; [7] the mean GCF MLT level varies between 0.5 and 2 pg/mL. [8]

Metabolism of melatonin

Both endogenous as well as exogenous MLT is metabolized by cytochrome P 450 mono-oxygenase enzymes, CYP1A2, in the liver. The half-life of MLT is 35 to 50 minutes and is mainly excreted through the kidneys. [10]

Melatonin receptors

MLT is a nontoxic, highly lipophilic indole and hence can penetrate through cell membranes and its compartments. [11] The mechanisms of action of MLT include the involvement of membrane receptors (MT1, MT2), cytosolic binding sites (MT3 and Calmodulin), and nuclear receptors of the retinoid related orphan nuclear hormone receptor (RZR/ROR) family. In addition, it also has receptor-independent activity and can directly scavenge free radicals. [12] Only the MT1 receptor has been identified in the mucosal cells of the oral cavity. Pharmacologically, melatonin receptors have been tentatively identified in the rat parotid gland. [6]


   Physiologic Functions of Melatonin Top


In animals, MLT controls the day-night cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions. Many biological effects of MLT are produced through the activation of MLT receptors whereas others are due to its role as a powerful antioxidant. The various physiologic functions and its possible mechanism are summarized in [Table 1].
Table 1: Summary of various functions of melatonin


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   Melatonin in Oral Health and Disease Top


Because of its production in extrapineal organs, including salivary glands, the present research portrays MLT as a cell protector rather than a hormone. MLT passively diffuses into the saliva and GCF and is released into the oral cavity. A significant correlation between concentrations of MLT in saliva and serum was reported with a general conclusion that salivary MLT concentration is a reliable index of serum MLT levels. [5] It has both receptor-mediated and receptor-independent actions in cells of the oral cavity. These various actions and their probable mechanisms have been discussed in the literature.

Melatonin and odontogenesis

MLT concentrations change in a specific manner during the lifespan of humans. MLT is a lipophilic hormone and crosses the placenta easily; therefore, prenatally, the fetus obtains melatonin from mother. [13] A study by Kivela et al. [13] found that MLT could be detected in infant blood during the first 2 weeks of life but there was no daily rhythm. The night-time rise in MLT concentrations is noted in the 6 th to 8 th week of life, and its circadian rhythm seems to be established at approximately 3 months of age. After this period, the MLT concentration continues to increase. The level of nocturnal MLT secretion reaches the highest in the ages between 4 and 7 years, and by the time of puberty, MLT concentrations slowly begin to decline. Interestingly, during this period, odontogenic apparatus undergoes crucial changes such as histogenesis, development, eruption, replacement and maturity. The results of various studies strongly suggest a physiological role of MLT in tooth development by regulating cellular processes in odontogenic cells, which may involve the modulation of mitochondrial function. [13]

A study by Ohtsuka et al. has demonstrated that complete lesion of the SCN led to a failure of the dentine incremental line appearance, and thus they presumed that this was associated with changes in hormones under tight circadian control. Because MLT is secreted in the SCN of the brain, it may be involved in the development of circadian dental formation. [14] Liu et al. conducted a study to investigate the effects of MLT on the proliferation and differentiation of rat dental papilla cells (rDPCs) in vitro and dentine formation in vivo. The study results demonstrated that MLT suppresses the proliferation and promotes the differentiation of rDPCs. Thus, they concluded that MLT affects the differentiation of rDPCs by the activity of mitochondrial complex I and complex IV. [15],[16]

Melatonin and Periodontal Health

Periodontal tissue is destroyed in the course of periodontitis by disproportionate immunologic responses to a triggering agent such as bacteria in plaque. Free radicals are released from the phagocytic cells, such as neutrophils and macrophages, and migrate to the inflamed area, significantly damaging the periodontal tissue. Lipid peroxidation is a major factor in the induction and progression of chronic periodontitis. Increased reactive oxygen species (ROS) captured by MLT and its metabolites in the inflamed area would be beneficial in reducing the degree of tissue damage. It may also influence fibroblast activity and bone regeneration by promoting osteoblast differentiation and bone formation. [11]

Almughrabi et al. compared salivary and GCF MLT levels in four groups of patients, i.e. healthy periodontium, simple gingivitis, chronic periodontitis, and aggressive periodontitis. The MLT levels were inversely related to the severity of periodontal destruction. [17] Cutando et al. demonstrated the use of melatonin in suppressing the periodontal disease in diabetic patients because they are more predisposed to periodontitis. Before the use of MLT, patients had significantly elevated salivary levels of alkaline and acid phosphatase as well as higher values of osteopontin (bone sialoprotein) and osteocalcin compared to nondiabetic controls. Following the topical application of MLT (1% orabase cream formula) to the gingiva once daily for 20 days, there were significant reductions in each of these parameters. Moreover, the gingival index and pocket depth were also reduced because of melatonin use. [18]

Collectively, many studies have revealed that MLT reduces the severity of the inflammatory response of periodontitis. The implication is that it may be of use as an agent to preserve the periodontal health, particularly in aged individuals when endogenous MLT levels diminish and in other situations such as smoking and diabetes.

Melatonin in osseous remodeling

Tooth extraction is commonly associated with extensive polymorphonuclear leukocyte infiltration to the site with massive ROS/reactive nitrogen species generation leading to elevated oxidative stress, including DNA damage. A study by Cutando et al. showed that topically applied MLT into the evacuated sockets following tooth removal from beagle dogs significantly reduced all parameters of oxidative stress in tissues. By limiting the tissue damage, MLT would limit the negative consequences of tooth removal and encourage more rapid healing of the wound. [19]

Melatonin in osteointegration of dental implants

A variety of substances are used to enhance peri-implant bone response, namely, growth factors, bone morphogenetic proteins, and recently, hormones such as growth hormones and MLT. There is some evidence that topical application of MLT may act as a biomimetic agent in the placement of endoasseous dental implants. Many studies have demonstrated the relationship between MLT and bone metabolism around implants and have shown that it acts as a local growth factor, with paracrine effects on cells. [20]

A study was done by Cutando et al. to assess the effect of MLT on osteointegration of dental implants. They added 1.2 mg lyophilized MLT powder after extraction of tooth from the mandible of beagle dogs and before implant placement. When the implant sites were examined 2 weeks later, the amount of bone in contact with the implant surface was significantly greater in the MLT-treated sockets than that in the controls. [20] A similar study by Munoz et al. demonstrated the synergistic effect on osseointegration of dental implants when both MLT and growth hormones were applied directly into the extraction sockets of dogs. [21]

Melatonin and salivary secretion

Based on new evidence, MLT may have a potential in the treatment of xerostomia. Its ability to regulate the secretory activity of the salivary glands may be exerted through a direct action on MLT receptors on the secretory units and partially depending on nitric oxide (NO) generation at the level of neuronal NO synthase. It has been also shown to evoke protein/amylase secretion from the parotid gland of the anesthetized rat. [22]


   Melatonin and Immunity Top


The link between MLT and the immune system is well known. Immune-suppression has been reported in several conditions where there is reduced MLT levels. In addition, certain immunosuppressive reactions caused by drugs are counteracted by MLT. In several species, pinealectomy or any experimental process which inhibits the synthesis and secretion of MLT induces a state of immunosuppression, this state being reversed by the exogenous administration. [23]

It has been found that MLT receptors are expressed on cell membrane of T lymphocytes. The activation of these receptors induces the release of cytokines such as interferon γ, interleukin (IL) 2, and opioid cytokines. MLT has been reported to increase the production of IL-1, 6, and 12 in human monocytes.[24] A relationship between IL-2 and MLT in immunomodulatory function has also been documented. It promotes the endogenic production of IL-2 and elevates its blood levels at night. It activates CD4+ lymphocytes by increasing the production of IL-2 and interferon γ and regulates immune functions by modulating the activity of CD4+ cells and monocytes.[23],[24]


   Melatonin and Oral Infections Top


MLT may have immunotherapeutic potential in viral and bacterial infections. The various possible mechanisms of its antibacterial, viral, and fungal actions are summarized in [Table 1]. In a study by Yavuz et al., levels of TNF-alpha and adhesion molecules in MLT-treated septic rats were reduced compared with those in untreated septic rats. [25] Considering these findings, MLT may have therapeutic benefits in Candida infection and in classic antimycotic treatment because of its immune-regulatory effects. Thus, it may also be useful as a topical and/or systemic treatment of oral candidiasis. [26]

Melatonin in oral mucositis

The antioxidant properties of MLT may be beneficial for the treatment of local inflammatory lesions and for accelerating the healing process. It has been shown to inhibit the inflammatory enzyme cyclooxygenase-2 (COX-2) by binding to the active sites of COX-1 and COX-2 indicating that it may act as a natural inhibitor of the function of these enzymes and thereby act as an endogenous inhibitor of inflammation. [27] MLT may also protect against ionizing radiation. The ulcerated and inflammatory lesions characteristic of radiation mucositis are a result of massive oxidative damage and the release of toxic cytokines. In light of these data, it would seem important to test MLT more extensively alone or in combination with other agents as a protector against radiotherapy and chemotherapy-mediated mucositis.


   Melatonin as Antineoplastic Agent Top


It has been shown that MLT exhibits oncostatic properties on a wide variety of tumors, including prostate, colorectal, neural, ovarian, breast, cervical cancers, sarcomas and hepatocarcinomas, melanomas, laryngeal carcinomas, and skin carcinomas. [28] Oral cancer in the initial stages commonly manifest as white or red patch in the oral cavity. When these lesions show dysplastic changes, they are referred as potentially malignant lesions. They include leukoplakia, erythroplakia, nicotine stomatitis, tobacco pouch keratosis, lichen planus, oral submucous fibrosis etc., By its actions against ROS, MLT may protect against precancerous oral lesions and conditions. [29]

The various mechanisms of cancer inhibition by MLT include: [30]

  • Antioxidant effect.
  • The regulation of estrogen receptor expression and transactivation.
  • Modulation of the enzymes involved in the local synthesis of estrogen.
  • Modulation of the cell cycle, differentiation, and apoptosis.
  • Inhibition of telomerase activity.
  • Antiangiogenesis.
  • Prevention of circadian disruption.
  • Activation of the immune system and epigenetic factors.
MLT may be successfully administered in medical oncology in the supportive care of untreatable advanced cancer patients and for the prevention of the side-effects of chemotherapy. It can also be used in the palliative treatment of cancer due to its anticachetic, antiasthenic, and thrombopoietic properties. [31] The regular administration of the indolamine induces significant decline in the frequency of cachexia, asthenia, thrombocytopenia, chemotherapy-induced lymphocytopenia, stomatitis, cardiotoxicity and neurotoxicity. [32]

Advantages of melatonin as a therapeutic agent

MLT has the following advantages as a safe therapeutic agent: [32]

  • It is endogenously produced.
  • It is nontoxic.
  • Diffuses rapidly into all cells and body fluids.
  • Penetrates all subcellular compartments.
  • Generally devoid of pro-oxidant actions.
  • Stimulates a number of antioxidant enzymes.
  • It could be applied directly on oral mucosa.

   Conclusion Top


Recent studies have brought to light that MLT, the chemical of darkness, has a role in oral health and disease. It may have clinical applications in reducing oral diseases, limiting tissue damage by free radicals, stimulating the immune response, reducing the loss of alveolar bone, promoting the regression of symptoms of viral infection, impeding local inflammatory lesions, and possible treatment of potentially malignant disorders and oral cancer. The functional aspects of MLT in the oral cavity need additional research and may prove to be a fertile area for research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Almughrabi OM, Marzouk KM, Hasanato RM, Shafik SS. Melatonin levels in periodontal health and disease. J Periodont Res 2013;48:315-21.  Back to cited text no. 17
    
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Cutando A, Lopez-Valverde A. Gomezde Diego R, Aria-Santiago S, de Vincent- Jimenez J. Effect of gingival application of melatonin on alkaline and acid phosphatase, osteopontin and osteocalcin in patients with diabetes and periodontal disease. Med Oral Patol Oral Cir Bucal 2013;18:e657-63.  Back to cited text no. 18
    
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