- About this Journal ·
- Abstracting and Indexing ·
- Aims and Scope ·
- Annual Issues ·
- Article Processing Charges ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Recently Accepted Articles ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
International Journal of Dentistry
Volume 2012 (2012), Article ID 720185, 9 pages
Melatonin: A Novel Indolamine in Oral Health and Disease
Department of Periodontics, Narayana Dental College & Hospital, Nellore, Andhra Pradesh, Nellore 524002, India
Received 2 January 2012; Accepted 31 May 2012
Academic Editor: Ali I. Abdalla
Copyright © 2012 V. K. Chava and K. Sirisha. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This paper attempts to summarise the findings accumulated within the last few years concerning the hormone of darkness “melatonin.” Based on its origin, from the pineal gland until recently it was portrayed exclusively as a hormone. Due to its lipophilic nature, it is accessible to every cell. Thus, in the classic sense it is a cell protector rather than a hormone. Recent studies, by Claustrat et al. (2005), detected few extrapineal sources of melatonin like retina, gastrointestinal tract, and salivary glands. Due to these sources, research by Cutando et al. (2007), is trying to explore the implications of melatonin in the oral cavity, in addition to its physiologic anti-oxidant, immunomodulatory and oncostatic functions at systemic level that may be receptor dependent or independent. Recently, certain in vivo studies by Shimozuma et al. (2011), detected the secretion of melatonin from salivary glands further emphasising its local activity. Thus, within our confines the effects of melatonin in the mouth are reviewed, adding a note on therapeutic potentials of melatonin both systemically and orally.
In light of the growing evidence, researchers are attempting to understand how the body naturally “turns off” inflammation. Melatonin (N-acetyl-5-methoxytryptamine) is one such powerful hormone derived from an essential amino acid tryptophan . It has various local and systemic functions playing a critical role in controlling inflammatory reactions. It is predominantly synthesised and secreted from pineal gland and other extrapineal sources like retina, gastrointestinal tract, lens, and immune system cells . The effects of melatonin were described in 1917 but were first isolated from bovine pineal gland and structurally identified in 1958 by Lerner and colleagues . Melatonin derives its name from serotonin, based on its ability to blanch the skin of amphibians . The unique, highly lipophilic nature of melatonin makes it accessible to every cell. It is found in high concentrations in the bone marrow, intestine, and at the sub-cellular level in the mitochondria and nucleus . Recently, its presence is detected in saliva and gingival crevicular fluid. Melatonin is said to play a significant role in protecting the oral cavity through its antioxidant, immunomodulatory, oncostatic, and other functions . Based on this evolving evidence, an attempt is made to review melatonin’s synthesis, effects and proposed therapeutic potentials.
Pinealocytes are responsible for melatonin production through a series of well-known reactions [7, 8]. It requires polysynaptic activation of beta-adrenergic receptors, which are indirectly regulated by neural stimulus from suprachiasmatic nucleus (SCN). Information on light/dark environments is transmitted via the retinohypothalamic tract to the suprachiasmatic nucleus. Thereafter an electrical neural signal is transferred to the upper thoracic cord and superior cervical ganglia after which it is conveyed from the postganglionic sympathetic fibres to the pineal gland . These postsynaptic terminals release norepinephrine which activates adrenergic receptors in the pinealocyte membrane. Pinealocytes take up tryptophan from the blood followed by the enzymatic reactions as shown in Figure 1, contributing to the synthesis of melatonin with the rate limiting enzyme being N-acetyltransferase (AANAT). Once produced, melatonin is quickly discharged into the capillary bed in the pineal gland and possibly directly into cerebrospinal fluid of third ventricle .
3. Melatonin Receptors
Melatonin has specific membrane and nuclear receptors that have been cloned and three subtypes have been identified [11, 12]. They were initially named Mel-1a, and Mel-1b, Mel-1c . The Mel-1a receptor gene has been mapped to human chromosome 4q35.1. Its primary expression is in the pars tuberalis of the pituitary gland and suprachiasmatic nucleus. Mel-1b has been mapped to chromosome 11q21-22, and its main expression is in the retina and brain. Mel-1c is not found in mammals. Mel-1a, Mel-1b are now renamed as MT1 and MT2 by International Union of Basic and Clinical Pharmacology (IUPHAR) . These two are members of a group of membrane receptors known as G-protein-coupled receptors that share a large part of amino acid sequences. The recently discovered MT3 receptor is a cytosolic enzyme, quinone reductase. Using gene knockout technology results to date suggests that the phase-shifting receptor is MT2, while MT1 is associated with acute suppression of suprachiasmatic nucleus electrical activity in addition to its important actions within the pars tuberalis; MT1 potentiates adrenergic vasoconstriction and MT2 modulates dopamine release in the retina [15–17].
4. Circadian Rhythm
The rhythmic production of melatonin is a consequence of neural impulses from the biologic clock, that is, from SCN and hypothalamus [1, 18]. It is known as the “chemical expression of darkness” as most of its synthesis occurs during night . In healthy individuals, peak serum melatonin levels are seen between 12.00 a.m–2.00 a.m. and 2.00–4.00 a.m, with minimum secretion occurring during the day 12.00 p.m–2.00 p.m . Following its secretion unbound melatonin diffuses passively into the saliva and oral mucosa to enter the oral cavity . So, salivary melatonin represents the percentage of free melatonin . The presence of melatonin in saliva is confirmed by several techniques such as automated solid phase extraction, high-performance liquid chromatography, and fluorescence detection . Salivary melatonin levels (2–4 pg/mL)  form 24–33% of the plasma melatonin levels . Factors such as smoking, exposure to light, alcohol consumption, and aging lower the levels of salivary melatonin with no variability in terms of gender . Recent evidence has observed its presence in the gingival crevicular fluid (GCF). GCF melatonin levels are 60% lower than serum levels and 30% lower than salivary levels . Measurement of salivary melatonin is a reliable technique to monitor the circadian rhythms of melatonin.
5. Physiological Functions
Since its discovery, melatonin has shown to have a variety of important functions in all species . These systemic and oral functions are indeed related to its hormonal properties as shown in Table 1.
5.1. Effects in Oral Cavity
Current research portrays melatonin as a cell protector rather than a hormone, due to its presence in extra-pineal organs including oral cavity . It passively diffuses into the oral cavity and is released into the saliva . A significant correlation between concentrations of melatonin in saliva and serum was reported with a general conclusion that melatonin concentration is a reliable index of serum melatonin levels .
6. Role of Melatonin in Oral Cancerous Lesions
Melatonin plays a pivotal role in many inflammatory processes of oral cavity and thus is effective in treating pathologies  like squamous cell carcinoma and epidermoid carcinoma. In relation to oral cancer, it is speculated that exogenous restoration of melatonin receptor 1a inhibited the growth of oral squamous cell carcinoma cells, lacking its expression . By its actions against ROS, melatonin may protect against precancerous oral diseases like leukoplakia and lichen planus [32, 33]. Melatonin also counteracts the negative effects of immunosuppressive drug therapy by acting on T-helper lymphocytes, lymphokines such as gamma interferon and IL-2 .
7. Role of Melatonin in Tooth Development
Melatonin may play a role in physiologic tooth development and growth by regulation of odontogenic cells in tooth germs . Immunohistochemical analysis revealed that melatonin 1a receptor (Me 1a R) was expressed in secretory ameloblasts, the cells of stratum intermedium and stellate reticulum, external dental epithelial cells, odontoblasts, and dental sac cells. Seasonal variation in the release of melatonin was associated with the changes in development of caries in hamsters .
8. Role of Melatonin in Inflammatory Conditions of the Oral Cavity
GCF melatonin levels play a significant role in periodontal disease. The pathogenesis of periodontitis is related to increased oxidative stress, which in turn leads to tissue damage and bone loss. The antioxidative and free radical scavenging action of melatonin may reduce this tissue damage . In addition, the positive effects of melatonin and its derivatives on inflammatory mediators and bone cells may be beneficial in improving periodontal health. Recent evidence  proved that salivary melatonin levels may vary according to the degree of periodontal disease. A negative association was found between salivary melatonin levels and periodontal disease severity. Consequently, decreased saliva and melatonin production with age predisposes older individuals to increased risk of oral and periodontal diseases. Dental procedures including tooth extraction may result in local inflammation and oxidative stress in the oral cavity. Upon local administration, the antioxidant action of melatonin may be useful in counteracting this oxidative stress [38, 39].
9. Role of Melatonin in Osseointegration and Regeneration
Melatonin was reported to stimulate the growth of new bone around implants in the tibia of rats . It has biologic significance in terms of osseointegration around implants. 2 weeks after implant insertion, melatonin significantly increased all parameters of osseointegration like bone to implant contact (BIC), total peri-implant bone, interthread bone, and new bone formation. In general, implants impregnated with topical melatonin at the time of placement showed more trabecular bone and higher trabecular density at implant contact [40, 41]. Osseointegration was reported to be more effective when melatonin was mixed with collagenised porcine bone [42, 43]. Melatonin at micro-molecular concentration promotes the proliferation of human mandibular cells (HOB-M) and cells of a human osteoblastic cellular line (SV-HFO). This effect is dose dependent and is maximum at concentrations of 50 micrometers . At concentrations ranging from 5 to 500 micrometers, melatonin lowers the expression of mRNA from the RANK and increases levels of both OPG as well as mRNA from the OPG in preosteoblast cell lines . Due to these actions on bone, its use as a biomimetic agent during endosseous dental implant surgery is proposed .
10. Role in Reducing Toxicity due to Dental Materials
Several cytotoxic and genotoxic effects of dental methacrylate monomers promote oxidative processes. Melatonin’s antioxidative action may protect against these effects by reducing oxidative DNA damage induced by methacrylates . Melatonin when used as a component of dental materials exhibited biocompatibility without altering the properties of these dental materials. Alternatively, the regular use of melatonin oral rinse may reduce the side effects of methacrylate monomers .
11. Role in Modification of Salivary Components
Novel evidence proposed that melatonin induced protein synthesis in the rat parotid gland and thereby affects glandular activity. This effect is MT-1- and MT-2-receptor-mediated and is primarily dependent on nitric oxide generation via the activity of neuronal-type nitric oxide synthase. This enzyme probably originated from parenchymal cells of the parotid gland. This novel action of melatonin may increase its clinical implications in the treatment of xerostomia, caries, periodontitis, oral mucosal infections, salivary gland inflammation, and wound healing . Summary of the Effects of melatonin in the oral cavity is shown in (Table 2).
12. New Sources of Melatonin
The previously mentioned finding put forth the quest for new sources of melatonin in the oral cavity. They evaluated the expression of melatonin-synthesising enzyme aryl-alkyl-amine N-acetyl transferase (AANAT) and hydroxyl indole-O-methyl transferase (HIONT) mRNA in rat submandibular gland by quantitative reverse transcription polymerase chain reaction. They observed expression of AANAT in the epithelial cells of striated ducts in rat salivary glands and expression of AANAT, HIONT, and melatonin in epithelial cells of striated ducts in human submandibular glands. In addition, the expression of most potent melatonin receptor (melatonin 1a) in rat buccal mucosa was confirmed . Melatonin at physiologic concentrations increased nerve growth factor synthesis in mouse submandibular gland . So, these oral sources of melatonin may alter salivary melatonin levels and thereby promote better oral health. So, without doubt all these actions have important consequences at the time of treatment of our high-risk dental patients who have in one way or the other an altered immunological system.
13. Therapeutic Potential of Melatonin
The antioxidant and free radical scavenging properties of melatonin might justify its therapeutic use in the treatment of disease like Parkinson’s disease , Alzheimer’s disease , epilepsy , infections, and inflammatory disorders . Melatonin is a known antineoplastic agent used in the treatment of cancers of lungs, kidney, prostate gland, stomach, and intestine [55, 56]. Melatonin can also be used in the palliative treatment of cancer due to its anticachetic, antiasthecnic, and thrombopoietic properties . It is a proven powerful cytostatic drug in vitro as well as in vivo. It induces apoptosis in human neuroblastoma cells and inhibits cell growth of glioma cells [55, 58, 59]. A favourable effect of local application of melatonin in the alveolar sockets following molar and premolar extractions was seen in beagle dogs . Melatonin protects the oral cavity and gastrointestinal tract from conditions such as stomatitis, oesophagitis, and peptic ulcer . Melatonin is a novel oesophageal protector acting through COX/Prostaglandin and NOS/NO systems and via activation of sensory nerves . Novel evidence implicates that melatonin may have potential to treat xerostomia by evoking protein/amylase secretion from the parotid gland of anaesthetised rats . In hamsters, the quantity of melatonin consumed in foodstuffs may influence caries incidence . Caries incidence is also found to be less common in winter and autumn when melatonin levels are maximum . Oral melatonin is widely used to reduce the subjective symptoms of jet lag . Melatonin was also found to be useful as a sedative, hypnotic, and anxiolytic. Its use as an oral sedative in dentistry is now being proposed .
14. Therapeutic Protocols Proposed for Melatonin
Beneficial antioxidant effects of low doses of melatonin (10 mg/day) are shown in several chronic diseases such as rheumatoid arthritis , primary essential hypertension in elderly patients (5 mg/day) , type 2 diabetes in elderly patients (5 mg/day) , and females suffering from infertility (3 mg/day) . A recent study reported beneficial effects of high doses of melatonin (20 mg/kg) for inhibiting apoptosis and liver damage resulting from oxidative stress in malaria, which could be a novel approach in the treatment of this disease . A formulation containing 2.5 mg melatonin and 100 mg SB-73 (a mixture of magnesium phosphate, fatty acids, and protein extracted from aspergillus oryzae) promoted regression of symptoms of herpes virus infection . The effect of melatonin on the ingestion and destruction of C. albicans by the ring dove (streptopelia risoria) at different durations of incubation (30–60 mins) with physiological (50 pgmL−1 diurnal and 300 pgmL−1 nocturnal) as well as with a pharmacological concentration 100 μm of melatonin showed a dose-dependent effect with decrease in superoxide anion levels after incubation .
15. Negative Effects of Melatonin
Melatonin is a potent adjunctive agent in the treatment of cancer and immune deficiency. However, poorly timed administration can produce opposite effects. Melatonin injections given in the morning stimulate tumour growth, whereas same doses given in the mid-afternoon have no effect but in the evening have a retarding effect [72, 73]. Melatonin administration may unduly prolong the nocturnal melatonin rise or that is given throughout the day may exacerbate bipolar and classic depression [74, 75]. Some people with depression may suffer from a low-melatonin syndrome . Animal studies have shown that moderately large doses of melatonin (equivalent to 30 mg in adult humans) increase light induced damage to retinal photoreceptors . Melatonin caused atherosclerosis in the aorta in hypercholesterolemic rats by suppressing LDL-receptor metabolic pathways . Preliminary animal studies suggest that melatonin may accelerate the development of autoimmune conditions .
Traditionally, melatonin was considered as the principal secretory hormone of pineal gland. Its profound systemic effects as a cell protector stimulated the quest for other extrapineal sources and functions. Novel evidence brought to light that this chemical of darkness has oral sources and implications. Based on this evidence, this paper attempts to concise the role of melatonin in oral health and disease mentioning a note on its therapeutic potential. Further studies need to focus their attention on therapeutic uses of melatonin as a coadjuvant in oral hygiene aids and as an antimicrobial in local therapy to promote it as a natural inhibitor of inflammation.
The authors would like to thank the librarian Mr. sastry for his support in collecting the articles for the paper. The study was self-funded by the authors and there was no external funding from any organization for this study.
- A. Kalsbeek and R. M. Buijs, “Output pathways of the mammalian suprachiasmatic nucleus: coding circadian time by transmitter selection and specific targeting,” Cell and Tissue Research, vol. 309, no. 1, pp. 109–118, 2002.
- B. Claustrat, J. Brun, and G. Chazot, “The basic physiology and pathophysiology of melatonin,” Sleep Medicine Reviews, vol. 9, no. 1, pp. 11–24, 2005.
- A. B. Lerner, J. D. Case, Y. Takahashi, T. H. Lee, and W. Mori, “Isolation of melatonin, the pineal gland factor that lightens melanocytes,” Journal of the American Chemical Society, vol. 80, no. 10, p. 2587, 1958.
- C. P. Mc Cord and F. P. Allen, “Evidence associating pineal gland function with alterations in pigmentation,” Journal of Experimental Zoology, vol. 23, no. 1, pp. 207–224, 1917.
- R. J. Reiter, S. D. Paredes, L. C. Manchester, and D. X. Tan, “Reducing oxidative/nitrosative stress newly discovered gene for melatonin,” Critical Reviews in Biochemistry and Molecular Biology, vol. 44, no. 4, pp. 175–200, 2009.
- A. Cutando, G. Gómez-Moreno, C. Arana, D. Acuña-Castroviejo, and R. J. Reiter, “Melatonin: potential functions in the oral cavity,” Journal of Periodontology, vol. 78, no. 6, pp. 1094–1102, 2007.
- D. Sugden and D. C. Klein, “A cholera toxin substrate regulates cyclic GMP content of rat pinealocytes,” Journal of Biological Chemistry, vol. 262, no. 16, pp. 7447–7450, 1987.
- R. J. Reiter, “Pineal melatonin: cell biology of its synthesis and of its physiological interactions,” Endocrine Reviews, vol. 12, no. 2, pp. 151–180, 1991.
- R. Y. Moore, “Neural control of the pineal gland,” Behavioural Brain Research, vol. 73, no. 1-2, pp. 125–130, 1996.
- R. J. Reiter, “Melatonin: clinical relevance,” Best Practice and Research, vol. 17, no. 2, pp. 273–285, 2003.
- D. Sugden, H. Pickering, M. T. Teh, and P. J. Garratt, “Melatonin receptor pharmacology: toward subtype specificity,” Biology of the Cell, vol. 89, no. 8, pp. 531–537, 1997.
- J. M. Guerrero, D. Pozo, S. Garcia-Maurino, C. Osuna, P. Molinero, and J. R. Calvo, “Involvement of nuclear receptors in the enhanced IL-2 production by melatonin in Jurkat cells,” Annals of the New York Academy of Sciences, vol. 917, pp. 397–403, 2000.
- S. M. Reppert, “Melatonin receptors: molecular biology of a new family of G protein-coupled receptors,” Journal of Biological Rhythms, vol. 12, no. 6, pp. 528–531, 1997.
- M. L. Dubocovich, D. P. Cardinali, B. Guardiola-Lemailre, et al., “Melatonin receptors,” in IUPHAR Compendium of Receptor Characterization and Classification, pp. 187–193, IUPHAR Media, London, UK, 1998.
- S. M. Reppert, D. R. Weaver, and C. Liu, “Nature's knockout: the Mel1b receptor is not necessary for reproductive and circadian responses to melatonin in Siberian hamsters,” Molecular Endocrinology, vol. 10, no. 11, pp. 1478–1487, 1996.
- M. L. Dubocovich, M. A. Rivera-Bermudez, M. J. Gerdin, and M. I. Masana, “Molecular pharmacology, regulation and function of mammalian melatonin receptors,” Frontiers in Bioscience, vol. 8, pp. 1093–1108, 2003.
- C. Von Gall, J. H. Stehle, and D. R. Weaver, “Mammalian melatonin receptors: molecular biology and signal transduction,” Cell and Tissue Research, vol. 309, no. 1, pp. 151–162, 2002.
- R. M. Buijs and A. Kalsbeek, “Hypothalamic integration of central and peripheral clocks,” Nature Reviews Neuroscience, vol. 2, no. 7, pp. 521–526, 2001.
- D. C. Klein and R. Y. Moore, “Pineal N-acetyltransferase and hydroxyindole-O-methyltransferase: control by the retinohypothalamic tract and the suprachiasmatic nucleus,” Brain Research, vol. 174, no. 2, pp. 245–262, 1979.
- V. Simonneaux and C. Ribelayga, “Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters,” Pharmacological Reviews, vol. 55, no. 2, pp. 325–395, 2003.
- R. J. Reiter, “Normal patterns of melatonin levels in the pineal gland and body fluids of humans and experimental animals,” Journal of neural transmission. Supplementum, vol. 21, pp. 35–54, 1986.
- M. Czesnikiewicz-Guzik, S. J. Konturek, B. Loster, G. Wisniewska, and S. Majewski, “Melatonin and its role in oxidative stress related diseases of oral cavity,” Journal of Physiology and Pharmacology, vol. 58, no. 3, pp. 5–19, 2007.
- S. Romsing, F. Bokman, and Y. Bergovist, “Determination of melatonin in saliva using automated solid phase extraction, high performance liquid chromatography and florescence detection,” Scandinavian Journal of Clinical and Laboratory Investigation, vol. 66, no. 1, pp. 181–190, 2006.
- M. L. Laakso, T. Porkka-Heiskanen, A. Alila, D. Stenberg, and G. Johansson, “Correlation between salivary and serum melatonin: dependence on serum melatonin levels,” Journal of Pineal Research, vol. 9, no. 1, pp. 39–50, 1990.
- A. Cutando, G. Gómez-Moreno, J. Villalba, M. J. Ferrera, G. Escames, and D. Acuña-Castroviejo, “Relationship between salivary melatonin levels and periodontal status in diabetic patients,” Journal of Pineal Research, vol. 35, no. 4, pp. 239–244, 2003.
- H. J. Burgess and L. F. Fogg, “Individual differences in the amount and timing of salivary melatonin secretion,” PLoS ONE, vol. 3, no. 8, Article ID e3055, 2008.
- R. J. Reiter, “The mammalian pineal gland: structure and function,” American Journal of Anatomy, vol. 162, no. 4, pp. 287–313, 1981.
- O. Vakkuri, J. Leppaluoto, and A. Kauppila, “Oral administration and distribution of melatonin in human serum, saliva and urine,” Life Sciences, vol. 37, no. 5, pp. 489–495, 1985.
- O. Vakkuri, “Diurnal rhythm of melatonin in human saliva,” Acta Physiologica Scandinavica, vol. 124, no. 3, pp. 409–412, 1985.
- R. Nowak, I. C. McMillen, J. Redman, and R. V. Short, “The correlation between serum and salivary melatonin concentrations and urinary 6-hydroxymelatonin sulphate excretion rates: two non-invasive techniques for monitoring human circadian rhythmicity,” Clinical Endocrinology, vol. 27, no. 4, pp. 445–452, 1987.
- G. Gómez-Moreno, J. Guardia, M. J. Ferrera, A. Cutando, and R. J. Reiter, “Melatonin in diseases of the oral cavity,” Oral Diseases, vol. 16, no. 3, pp. 242–247, 2010.
- P. Chaiyarit, N. Ma, Y. Hiraku et al., “Nitrative and oxidative DNA damage in oral lichen planus in relation to human oral carcinogenesis,” Cancer Science, vol. 96, no. 9, pp. 553–559, 2005.
- M. A. Taubman, P. Valverde, X. Han, and T. Kawai, “Immune response: they key to bone resorption in periodontal disease,” Journal of Periodontology, vol. 76, no. 11, pp. 2033–2041, 2005.
- A. Cutando and F. J. Silvestre, “Melatonin: implications at the oral level,” Bulletin du Groupement international pour la recherche scientifique en stomatologie & odontologie, vol. 38, no. 3-4, pp. 81–86, 1995.
- S. Kumasaka, M. Shimozuma, T. Kawamoto et al., “Possible involvement of melatonin in tooth development: expression of melatonin 1a receptor in human and mouse tooth germs,” Histochemistry and Cell Biology, vol. 133, no. 5, pp. 577–584, 2010.
- J. C. Mechin and C. Toury, “Action of cariogenic diet on fixation and retention of skeleton and teeth strontium in rats,” Rev Mens Suisse Odontostomatol, vol. 20, no. 1, pp. 55–59, 1973.
- A. Cutando, P. Galindo, G. Gómez-Moreno et al., “Relationship between salivary melatonin and severity of periodontal disease,” Journal of Periodontology, vol. 77, no. 9, pp. 1533–1538, 2006.
- A. Cutando, C. Arana, G. Gómez-Moreno et al., “Local application of melatonin into alveolar sockets of beagle dogs reduces tooth removal-induced oxidative stress,” Journal of Periodontology, vol. 78, no. 3, pp. 576–583, 2007.
- A. Cutando, G. Gomez-Moreno, C. Arana, G. Escames, and D. Acuña-Castroviejo, “Melatonin reduces oxidative stress because of tooth removal,” Journal of Pineal Research, vol. 42, no. 4, pp. 419–420, 2007.
- I. F. Tresguerres, C. Clemente, L. Blanco, et al., “Effects of local melatonin application on implant osseointegration,” Clinical Implant Dentistry and Related Research, vol. 14, no. 3, pp. 395–399, 2012.
- J. L. Calvo-Guirado, G. Gómez-Moreno, A. Barone et al., “Melatonin plus porcine bone on discrete calcium deposit implant surface stimulates osteointegration in dental implants,” Journal of Pineal Research, vol. 47, no. 2, pp. 164–172, 2009.
- J. L. Calvo-Guirado, M. P. Ramírez-Fernández, G. Gómez-Moreno et al., “Melatonin stimulates the growth of new bone around implants in the tibia of rabbits,” Journal of Pineal Research, vol. 49, no. 4, pp. 356–363, 2010.
- A. Cutando, G. Gómez-Moreno, C. Arana et al., “Melatonin stimulates osteointegration of dental implants,” Journal of Pineal Research, vol. 45, no. 2, pp. 174–179, 2008.
- O. Nakade, H. Koyama, H. Ariji, A. Yajima, and T. Kaku, “Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro,” Journal of Pineal Research, vol. 27, no. 2, pp. 106–110, 1999.
- H. Koyama, O. Nakade, Y. Takada, T. Kaku, and K. H. W. Lau, “Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation,” Journal of Bone and Mineral Research, vol. 17, no. 7, pp. 1219–1229, 2002.
- P. A. Simon and Z. Watson, “Bio mimetic dental implants- new ways to enhance osteointegration,” Journal of the Canadian Dental Association, vol. 68, no. 5, pp. 286–288, 2002.
- J. Blasiak, J. Kasznicki, J. Drzewoski, E. Pawlowska, J. Szczepanska, and R. J. Reiter, “Perspectives on the use of melatonin to reduce cytotoxic and genotoxic effects of methacrylate-based dental materials,” Journal of Pineal Research, 2011.
- H. Cevik-Aras, T. Godoy, and J. Ekstrom, “Melatonin-induced protein synthesis in the rat parotid gland,” Journal of Physiology and Pharmacology, vol. 62, no. 1, pp. 95–99, 2011.
- M. Shimozuma, R. Tokuyama, S. Tatehara et al., “Expression and cellular localizaion of melatonin-synthesizing enzymes in rat and human salivary glands,” Histochemistry and Cell Biology, vol. 135, no. 4, pp. 389–396, 2011.
- A. Pongsa-Asawapaiboon, P. Asavaritikrai, B. Withyachumnarnkul, and A. Sumridthong, “Melatonin increases nerve growth factor in mouse submandibular gland,” Journal of Pineal Research, vol. 24, no. 2, pp. 73–77, 1998.
- J. C. Mayo, R. M. Sainz, D. X. Tan, I. Antolín, C. Rodríguez, and R. J. Reiter, “Melatonin and Parkinson's disease,” Endocrine, vol. 27, no. 2, pp. 169–178, 2005.
- M. A. Pappalla, R. J. Reiter, T. K. Bryant-Thomas, and B. Beggeler, “Oxidative mediated neurodegeneration in Alzheimer's diseases: melatonin and related antioxidant as neuroprotective agents,” Current Medicinal Chemistry, vol. 3, no. 1, pp. 233–243, 2003.
- V. Srinivasan, S. R. Pandi-Perumal, D. P. Cardinali, B. Poeggeler, and R. Hardeland, “Melatonin in Alzheimer's disease and other neurodegenerative disorders,” Behavioral and Brain Functions, vol. 2, p. 15, 2006.
- J. C. Mayo, R. M. Sainz, D. X. Tan et al., “Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages,” Journal of Neuroimmunology, vol. 165, no. 1-2, pp. 139–149, 2005.
- S. C. Miller, P. S. R. Pandi, A. I. Esquifino, D. P. Cardinali, and G. J. M. Maestroni, “The role of melatonin in immuno-enhancement: potential application in cancer,” International Journal of Experimental Pathology, vol. 87, no. 2, pp. 81–87, 2006.
- R. J. Reiter, D. X. Tan, and M. A. Pappolla, “Melatonin relieves the neural oxidative burden that contributes to dementias,” Annals of the New York Academy of Sciences, vol. 1035, pp. 179–196, 2004.
- P. Lissoni, “Is there a role for melatonin in supportive care?” Supportive Care in Cancer, vol. 10, no. 2, pp. 110–116, 2002.
- G. García-Santos, I. Antolín, F. Herrera et al., “Melatonin induces apoptosis in human neuroblastoma cancer cells,” Journal of Pineal Research, vol. 41, no. 2, pp. 130–135, 2006.
- V. Martin, F. Herrera, and P. Carrera-Gonzalez, “Intra cellular signalling pathways involved in the cell growth inhibition of glioma cells by melatonin,” Cancer Research, vol. 66, no. 2, pp. 1081–1088, 2006.
- S. J. Konturek, O. Zayachkivska, X. O. Havryluk, et al., “Protective influence of melatonin against acute oesophageal lesions involves prostaglandins, nitric oxide and sensory nerves,” Journal of Physiology and Pharmacology, vol. 58, no. 2, pp. 361–377, 2007.
- H. Ç. Aras and J. Ekström, “Melatonin-evoked in vivo secretion of protein and amylase from the parotid gland of the anaesthetised rat,” Journal of Pineal Research, vol. 45, no. 4, pp. 413–421, 2008.
- J. C. Mechin and C. Toury, “Action of cariogenic diet on fixation and retention of skeleton and teeth strontium in rats,” Revue d"odonto-stomatologie, vol. 20, no. 1, pp. 55–59, 1973.
- J. Waterhouse, T. Reilly, and G. Atkinson, “Jet-lag,” The Lancet, vol. 350, no. 9091, pp. 1611–1616, 1997.
- Petercop, “Melatonin, a novel oral sedative for dentistry,” Clinical Ontario Dentist, pp. 22–25, 2010.
- C. M. Forrest, G. M. Mackay, N. Stoy, T. W. Stone, and L. G. Darlington, “Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin,” British Journal of Clinical Pharmacology, vol. 64, no. 4, pp. 517–526, 2007.
- K. Kedziora kornatowska, K. Szwczyk-Golec, J. Czuczejko, H. Pawluk, and K. Van Marke de Lumen, “Antioxidative affects of melatonin administration in elderly primary essential hypertension patients,” Journal of Pineal Research, vol. 45, pp. 312–317, 2008.
- K. Kdziora-Kornatowska, K. Szewczyk-Golec, M. Kozakiewicz et al., “Melatonin improves oxidative stress parameters measured in the blood of elderly type 2 diabetic patients,” Journal of Pineal Research, vol. 46, no. 3, pp. 333–337, 2009.
- H. Tamura, A. Takasaki, I. Miwa et al., “Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate,” Journal of Pineal Research, vol. 44, no. 3, pp. 280–287, 2008.
- V. Srinivasan, D. W. Spence, A. Moscovitch et al., “Malaria: therapeutic implications of melatonin,” Journal of Pineal Research, vol. 48, no. 1, pp. 1–8, 2010.
- O. D. S. Nunes and R. D. S. Pereira, “Regression of herpes viral infection symptoms using melatonin and SB-73: comparison with acyclovir,” Journal of Pineal Research, vol. 44, no. 4, pp. 373–378, 2008.
- M. P. Terron, J. Cubero, C. Barriga, E. Ortega, and A.B. Rodriguez, “Phagocytosis of Candida albicans and superoxide anion levels in ring dove (Streptopelia risoria) heterophils: effect of melatonin,” Journal of Neuroendocrinology, vol. 15, no. 12, pp. 1111–1115, 2003.
- D. E. Blask, S. Cos, S. M. Hill, D. M. Burns, A. Lemus-Wilson, and D. S. Grosso, “Melatonin action on oncogenesis,” in Role of Melatonin and Pineal Peptides in Neuroimmunomodulation, R. J. Franschini and F. Reiter, Eds., pp. 233–240, Plenum, New York, NY, USA, 1991.
- H. Bartsch and C. Bartsch, “Effect of melatonin on experimental tumors under different photoperiods and times of administration,” Journal of Neural Transmission, vol. 52, no. 4, pp. 269–279, 1981.
- J. S. Carman, R. M. Post, R. Buswell, and F. K. Goodwin, “Negative effects of melatonin on depression,” American Journal of Psychiatry, vol. 133, no. 10, pp. 1181–1186, 1976.
- N. E. Rosenthal, D. A. Sack, and S. P. James, “Seasonal affective disorder and phototherapy,” Annals of the New York Academy of Sciences, vol. 453, pp. 260–269, 1985.
- J. Beck-Friis, B.F. Kjellman, and B. Aperia, “Serum melatonin in relation to clinical variables in patients with major depressive disorder and a hypothesis of a low melatonin syndrome,” Acta Psychiatrica Scandinavica, vol. 71, no. 4, pp. 319–330, 1985.
- A. F. Wiechmann and W. K. O'Steen, “Melatonin increases photoreceptor susceptibility to light-induced damage,” Investigative Ophthalmology and Visual Science, vol. 33, no. 6, pp. 1894–1902, 1992.
- A. Tailleux, G. Torpier, D. Bonnefont-Rousselot et al., “Daily melatonin supplementation in mice increases atherosclerosis in proximal aorta,” Biochemical and Biophysical Research Communications, vol. 293, no. 3, pp. 1114–1123, 2002.
- R. Mattsson, I. Hannsson, and R. Holmdahl, “Pineal gland in autoimmunity: melatonin dependent exacerbation of collagen induced arthritis in mice,” Autoimmunity, vol. 17, no. 1, pp. 83–86, 1994.
- K. Ganguly, P. Kundu, A. Banerjee, R. J. Reiter, and S. Swarnakar, “Hydrogen peroxide-mediated downregulation of matrix metalloprotease-2 in indomethacin-induced acute gastric ulceration is blocked by melatonin and other antioxidants,” Free Radical Biology and Medicine, vol. 41, no. 6, pp. 911–925, 2006.
- R. J. Reiter, D. Melchiorri, E. Sewerynek et al., “A review of the evidence supporting melatonin's role as an antioxidant,” Journal of Pineal Research, vol. 18, no. 1, pp. 1–11, 1995.
- D. X. Tan, L. C. Manchester, R. J. Reiter et al., “Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation,” Free Radical Biology and Medicine, vol. 29, no. 11, pp. 1177–1185, 2000.
- C. M. Cagnoli, C. Atabay, E. Kharlamova, and H. Manev, “Melatonin protects neurons from singlet oxygen-induced apoptosis,” Journal of pineal research, vol. 18, no. 4, pp. 222–226, 1995.
- D. Bongiorno, L. Ceraulo, M. Ferrugia, F. Filizzola, A. Ruggirello, and V. T. Liveri, “Localization and interactions of melatonin in dry cholesterol/lecithin mixed reversed micelles used as cell membrane models,” Journal of Pineal Research, vol. 38, no. 4, pp. 292–298, 2005.
- S. Aydogan, M. Betul Yerer, and A. Goktas, “Melatonin and nitric oxide,” Journal of Endocrinological Investigation, vol. 29, no. 3, pp. 281–287, 2006.
- I. Antolín, C. Rodriguez, R. M. Sáinz et al., “Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes,” FASEB Journal, vol. 10, no. 8, pp. 882–890, 1996.
- C. Rodriguez, J. C. Mayo, R. M. Sainz et al., “Regulation of antioxidant enzymes: a significant role for melatonin,” Journal of Pineal Research, vol. 36, no. 1, pp. 1–9, 2004.
- C. Tomás-Zapico and A. Coto-Montes, “A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes,” Journal of Pineal Research, vol. 39, no. 2, pp. 99–104, 2005.
- N. de la Rocha, A. Rotelli, C. F. Aguilar, and L. Pelzer, “Structural basis of the anti-inflammatory activity of melatonin,” Arzneimittel-Forschung/Drug Research, vol. 57, no. 12, pp. 782–786, 2007.
- J. M. Guerrero, D. Pozo, S. García-Mauriño, C. Osuna, P. Molinero, and J. R. Calvo, “Involvement of nuclear receptors in the enhanced IL-2 production by melatonin in Jurkat cells,” Annals of the New York Academy of Sciences, vol. 917, pp. 397–403, 2000.
- S. Garcia-Mauriño, M. G. Gonzalez-Haba, J. R. Calvo et al., “Melatonin enhances IL-2, IL-6, and IFN-γ production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes,” Journal of Immunology, vol. 159, no. 2, pp. 574–581, 1997.
- S. Garcia-Maurino, D. Pozo, J. R. Calvo, and J. M. Guerrero, “Correlation between nuclear melatonin receptor expression and enhanced cytokine production in human lymphocytic and monocytic cell lines,” Journal of Pineal Research, vol. 29, no. 3, pp. 129–137, 2000.
- A. Cutando, C. Arana, G. Gomez-Moreno, et al., “Melatonin plasma and salivary and lymphocyte subpopulation in periodontal patients,” Special Care Dentistry, vol. 24, p. 169, 2004.
- P. J. Lardone, A. Carrillo-Vico, M. C. Naranjo et al., “Melatonin synthesized by Jurkat human leukemic T cell line is implicated in IL-2 production,” Journal of Cellular Physiology, vol. 206, no. 1, pp. 273–279, 2006.
- R. J. Reiter, D. X. Tan, A. Korkmaz et al., “Light at night, chronodisruption, melatonin suppression, and cancer risk: a review,” Critical Reviews in Oncogenesis, vol. 13, no. 4, pp. 303–328, 2007.
- R. J. Reiter, “Mechanisms of cancer inhibition by melatonin,” Journal of Pineal Research, vol. 37, no. 3, pp. 213–214, 2004.
- M. P. Terron, J. Cubero, J. M. Marchena, C. Barriga, and A. Rodriguez, “Melatonin and aging: invitro effect of young and mature ring dove physiological concentrations of melatonin on the phagocytic functions of neutrophils from old ring dove,” Experimental Gerontology, vol. 37, no. 2-3, pp. 421–426, 2002.
- M. P. Terron, S. P. Parades, C. Barriga, E. Ortega, and A. B. Rodriguez, “Comparitive study of heterophil phagocytic function in young and old ring doves (Streptopelia risona) and its relationship with melatonin levels,” Journal of Comparative Physiology B, vol. 174, no. 5, pp. 421–427, 2004.
- J. A. Roth, B. G. Kim, W. L. Lin, and M. I. Cho, “Melatonin promotes osteoblast differentiation and bone formation,” Journal of Biological Chemistry, vol. 274, no. 31, pp. 22041–22047, 1999.
- H. Yasuda, “Bone and bone related biochemical examinations. Bone and collagen related metabolites. Receptor activator of NF-kappaB ligand (RANKL),” Clinical Calcium, vol. 16, no. 6, pp. 80–86, 2006.
- B. F. Boyce, E. M. Schwarz, and L. Xing, “Osteoclast precursors: cytokine-stimulated immunomodulators of inflammatory bone disease,” Current Opinion in Rheumatology, vol. 18, no. 4, pp. 427–432, 2006.
- E.-Y. Choi, J.-Y. Jin, J.-Y. Lee, J.-I. Choi, I. S. Choi, and S. J. Kim, “Melatonin inhibits Prevotella intermedia lipopolysaccharide-induced production of nitric oxide and interleukin-6 in murine macrophages by suppressing NF-κB and STAT1 activity,” Journal of Pineal Research, vol. 50, no. 2, pp. 197–206, 2011.