Sankari M, Meenakshi S. S. Melatonin in Periodontal Diseases: A Review. Biomed Pharmacol J 2019;12(1).
Manuscript received on :18-Dec-2018
Manuscript accepted on :28-Feb-2019
Published online on: 18-03-2019
Plagiarism Check: Yes
Reviewed by: Exbrayat Jean-Marie
Second Review by: Sameer Zope
Final Approval by: Dr. Patorn Piromchai

How to Cite    |   Publication History
Views Views: (Visited 70 times, 1 visits today)   Downloads PDF Downloads: 79
Melatonin in Periodontal Diseases: A Review

M. Sankari and S. Swarna Meenakshi  

Department of Periodontics, Saveetha Dental College, Saveetha University, Saveetha Institute of Medical and Technical Sciences (SIMATS) Chennai, India.

Corresponding Author E-mail:



Melatonin is a substance that is secreted by multiple organs in Humans. In addition to playing a role in the regulation of the circadian cycle, it is also known to have antioxidant, antiinflammatory, and antioncotic effects on human tissues. Oral cavity is an easy target for many conditions such as periodontitis, mucositis, cancers, and cytotoxicity from various drugs or biomaterials. Research on melatonin as a therapeutic agent has suggested that it is effective in treating the aforementioned pathologic conditions effectively. Furthermore, melatonin tends to favour bone regeneration by behaving as an osteoconductive scaffold. The aim of this review is to summarize the uses and potential of melatonin in management of periodontal diseases.


Anti Oxidant; Bone Formation; Inflammation; Melatonin; Oral Cavity; Periodontitis

Download this article as: 
Copy the following to cite this article:

Sankari M, Meenakshi S. S. Melatonin in Periodontal Diseases: A Review. Biomed Pharmacol J 2019;12(1).

Copy the following to cite this URL:

Sankari M, Meenakshi S. S. Melatonin in Periodontal Diseases: A Review. Biomed Pharmacol J 2019;12(1). Available from:


Periodontitis is a chronic inflammatory disease affecting the supporting tissues of the tooth which are collectively called, the periodontium.1 The main etiology for periodontal disease is  the microbes in the dental plaque. These microorganisms are capable of synthesizing enzymes that could damage the host tissue and in response to these microbes the host tries to wade off the infection by activating the innate and adaptive immune systems. Activation of the innate and adaptive immune system tries to counteract the microbial attack, but at the same time causes major destruction of the host tissue by producing high amounts of inflammatory cytokines, pro osteoclastogenic factors, and matrix metalloproteinases.One of the important factor in worsening the damage to the existing periodontium is the generation of free radicals and reactive oxygen species, which could originate from the bacteria and also from neutrophils which are the first line of defence.3,4 Furthermore, there is an imbalance between the oxidant and antioxidant systems.

Melatonin (N-acetyl-5-methoxy tryptamine) is a substance which is secreted by multiple organs such as the pineal gland, retina, bone marrow, the gastro-intestinal tract, whose main role is to regulate the circadian rhythm (day and night cycles).5 It plays an anti-inflammatory, anti-oncotic, and immunomodulatory role by acting as a scavenger of free-radicals by interacting with cell membrane and intracellular proteins.6

Melatonin for the Treatment of Periodontal Disease

When it comes to the oral cavity, the antioxidant nature of melatonin makes it a favourite substance. Melatonin enters the oral cavity by diffusing into the saliva from the blood stream. Since a majority of melatonin remains bound to serum albumin, its level in the saliva is one third the level in blood.It exerts its effects by interacting with melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) receptors on cells.8,9 Its antiinflammatory properties have been studied and reported on human gingival fibroblasts.10

Furthermore, intraperitoneal administration of melatonin has proved to successfully reduce the severity of periodontitis in diabetic rats.11 Similarly, topical application of melatonin in diabetic patients resulted in down regulation of proinflammatory factors thereby diminishing the progression of bone loss due to periodontitis.12-14 Similar Studies in diabetic animal models have shown a diminished oxidative stress index and reduced alveolar bone loss with the use of melatonin.

Cyclooxygenase (COX)-2 is a key enzyme that catalyzes the two sequential steps responsible for biosynthesis of prostaglandins (PGs) from arachidonic acid which plays a critical role in the inflammatory response, the overexpression of which has been associated with several types of pathology, including periodontal disease. Studies have shown that melatonin was capable of exerting a suppressive effect on Cox-2.15 In addition to the above mentioned , melatonin down regulates proinflammatory factors such as C reactive protein(CRP), interleukin 6 and TNF alpha,12 receptor activators of nuclear factor kappa-B ligand/osteoprotegrin ratios thereby causing a decrease in periodontal inflammation.

Studies have shown that salivary acid phosphatase, alkaline phosphatase, osteopontin and osteocalcin levels had significantly improved following topical administration of melatonin.13

This makes melatonin a potential therapeutic agent against periodontal diseases. They could be used as an adjunct to scaling, root planning and surgical debridement to improve the outcomes of periodontal therapy.

Melatonin as an Antioxidant and free Radical Scavenger

Melatonin is a potent antioxidant and scavenger of free radicals.16,17An important characteristic that distinguishes melatonin from other free radical scavengers is that even the metabolites of melatonin have the capability to act as scavengers. This is termed as “Cascade reaction”.16 Kara et al in their study suggested that melatonin could stimulate various antioxidant enzymes.18

Melatonin acts principally by electron donation.19 Melatonin has the capability of donating one or more electrons to free radicals thereby detoxifying them, during this process there is also formation of certain metabolites such as-  c3OHM, AFMK, and AMK, also have similar scavenging capabilities.20 After donating an electron to OH•, melatonin becomes a free radical itself, the indolyl radical cation with very low reactivity, thereby being non toxic to cells.21

Melatonin as A Promoter of Bone Formation

Melatonin is known to stimulate the proliferation of osteoblasts and promote bone formation.22 It acts as osteoconductive scaffold.23,24 Clafshenkel et al in 2012 developed a novel calcium aluminate-melatonin material and used it as a scaffold in calvarial defects in animal models and found a significant amount of bone regeneration.25 A study by Kose et al showed that myeloperoxidase activity, number of osteoclasts, density of neutrophils and also RANKL/Osteoprotegrin ratio were increased in periodontitis which could be the cause for increased alveolar bone loss.11 Roth et al studied the effects of melatonin administration on myeloperoxidase activity and alveolar bone destruction and found that there was a reduction in gingival tissue myeloperoxidase levels and further stimulated the proliferation of osteoblasts to promote bone formation.22

Cudanto et al. evaluated the effectiveness of topical melatonin (1% orabase cream formulation). He tested it by applying it onto the surface of attached gingiva for 20 days in diabetic individuals with periodontitis and healthy individuals with periodontitis and observed a significant decrease in clinical parameters such as gingival index and probing depth, biochemical parameters such as alkaline and acid phosphatase enzyme levels and RANKL levels , OPG levels.13

Melatonin as an Anti Inflammatory Agent

Inflammation is a normal and an essential response to any insult.19 As discussed earlier, melatonin interacts directly with COX-2 and also blocks the transcriptional factors that triggers the production of pro inflammatory cytokines. Mohmood et al first showed the anti-inflammatory effects of melatonin in a dose-dependent manner in rats.26

Melatonin as an Anti Microbial Agent

Melatonin possesses antimicrobial properties against numerous bacteria and virus.27,28 A recent study by Wei Zhou et al was the first of its kind to evaluate the effects of melatonin and a melatonin receptor agonist Ramelteon against Porphyromonas gingivalis.29 They concluded that both melatonin and its receptor agonist were capable of inhibiting biofilm formation, decreased the viability of Porphyromonas gingivalis, showed an antii nflammatory response by acting on the lipopolysaccharide. They also found a reduction in proinflammatory IL 6 and IL 8 , inhibition of mRNA expression of gingipains while having no cytotoxicity towards Human gingival fibroblasts.

Melatonin as A Marker in Periodontal Disease

Cutando,7 Almughrabhi30 and Gómez-Moreno31 in their studies stated that the levels of salivary and serum melatonin differed with varying degrees of periodontitis. They found an inverse correlation between the levels of salivary melatonin and periodontal destruction. The higher the destruction , the lower were the levels of melatonin. Bertl et al found that salivary melatonin levels improved significantly after non surgical periodontal therapy in patients with periodontitis.32


Melatonin administration shows promise in the management of periodontal diseases. It plays essential roles in modulating various immune responses and most of the studies have been favourable to usage of melatonin for therapy. However, more clinical trials and animal studies where melatonin is locally delivered to the target site are required to ascertain whether melatonin has potential as a therapeutic agent.


We thank all the faculty in our Department of Periodontics for their guidance

Conflict of Interest

There is no conflict of Interest.


  1. Listgarten M. A. Pathogenesis of periodontitis. Journal of Clinical Periodontology. 1986;13(5):418–430.
  2. Zambon J. J., Reynolds H., Fisher J. G et al. Microbiological and immunological studies of adult periodontitis in patients with non insulin-dependent diabetes mellitus. J Periodontol. 1988;59:23–31.
  3. Gustafson A., Asman B. Increased release of free oxygen radicals from peripheral neutrophils in adult periodontitis after Fcc-receptor stimulation. J Clin Periodontol. 1996;23:38–44.
  4. Kimura S., Yonemura T., Kaya H. Increased oxidative product formation by peripheral blood polymorphonuclear leukocytes in human periodontal disease. J Periodontal Res. 1993;28:197–203.
  5. Siu A. W., Maldonado M., Sanchez-Hidalgo M., Tan D. X., Reiter R. J. Protective effects of melatonin in experimental free radical-related ocular diseases. J Pineal Res. 2006;40:101e9.
  6. Cutando A., Aneiros-Fernandez J., Lopez-Valverde A., Arias- Santiago S,. Aneiros-Cachaza J., Reiter R. J. A new perspective in Oral health: potential importance and actions of melatonin receptors MT1, MT2, MT3, and RZR/ROR in the oral cavity. Arch Oral Biol. 2011;56:944e50.
  7. Cutando A., Galindo P., Gomez-Moreno G., Arana C., Bolanos J., Acuna-Castroviejo D., et al. Relationship between salivary melatonin and severity of periodontal disease. J Periodontol. 2006;77:1533e8.
  8. Slominski R. M., Reiter R. J., Schlabritz-Loutsevitch N., Ostrom R. S., Slominski A. T. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol. 2012; 351:152e66.
  9. Garcia-Maurino S., Gonzalez-Haba M. G., Calvo J. R., Rafii-El- Idrissi M., Sanchez-Margalet V., Goberna R., et al. Melatonin enhances IL-2, IL-6 and IFN-gamma production by human circulating CD4fl cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes. J Immunol. 1997;159:574e81.
  10. Gomez-Florit M., Ramis J. M., Monjo M. Anti-fibrotic and anti-inflammatory properties of melatonin on human gingival fibroblasts in vitro. Biochem Pharmacol. 2013;86:1784e90.
  11. Kose O., Arabaci T., Kara A., Yemenoglu H., Kermen E., Kizildag A., et al. Effects of melatonin on oxidative stress index and alveolar bone loss in diabetic rats with periodontitis. J Periodontol. 2016;87:82e90.
  12. Cutando A., Montero J., Gomez-de Diego R., Ferrera M. J., Lopez- Valverde A. Effect of topical application of melatonin on serum levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in patients with type 1 or type 2 diabetes and periodontal disease. J Clin Exp Dent. 2015;7:e628e33.
  13. Cutando A., Lopez-Valverde A., Gomez-de-Diego R., Arias- Santiago S., de Vicente-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:e657e63.
  14. Cutando A., Lopez-Valverde A., de Diego R. G., de Vicente J., Reiter R., Fernandez M. H., et al. Effect of topical application of melatonin to the gingiva on salivary osteoprotegerin, RANKL and melatonin levels in patients with diabetes and periodontal disease. Odontology. 2014;102:290e6.
  15. Tekbas O. F., Ogur R., Korkmaz A et al. Melatonin as an antibiotic: new insights into the actions of this ubiquitous molecule. J Pineal Res. 2008;44:222–226.
  16. Arnao M. B., Hernandez−Ruiz J. The physiological function of melatonin in plants. Plant Signal Behav. 2016;1(3):89–95.
  17. Tan D. X., Chen L. D., Poeggeler B., Manchester L. C., et al. Melatonin a potent endogenous hydroxyl radical scavenger. Endocrine J. 1993;1:57–60.
  18. Kara A., Akman S., Ozkanlar S., et al. Immune modulatoryand antioxidant effects of melatonin in experimental periodontitis in rats. Free Radic Biol Med. 2013;55:21−26.
  19. Anwar M. J., Muhammad B. Y., Bader A. A., Abdulghani M., Mahmood D., Haider M. An insight into the scientific background and future perspectives for the potential uses of melatonin. Egyptian Journal of Basic and Applied Sciences. 2015;2:139-152.
  20. Reiter R. J., Tan D. X., Manchester L. C.,Terron M. P., Flores L. J., Koppisepi S. Medical implications of melatonin: Receptor-mediated and receptor-independent actions. Advances in Medical Sciences. 2007;52:11-28.
  21. Galano A., Tan D. X., Reiter R. J. Melatonin as a natural ally against oxidative stress: A physicochemical examination. Journal of Pineal Research. 2011;51:1-16.
  22. Roth J. A., Kim B. G., Lin W. L., Cho M. I. Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem. 1999;274:22041e7.
  23. Luchetti F., Canonico B., Bartolini D., Arcangeletti M., Ciffolilli S., Murdolo G., et al. Melatonin regulates mesenchymal stem cell differentiation: a review. J Pineal Res. 2014;56:382e97.
  24. Shino H., Hasuike A., Arai Y., Honda M., Isokawa K., Sato S. Melatonin enhances vertical bone augmentation in rat calvaria secluded spaces. Med Oral Patol Oral Cir Bucal. 2016;21:e122e6.
  25. Clafshenkel W. P., Rutkowski J. L., Palchesko R. N., Romeo J. D., McGowan K. A., Gawalt E. S., et al. A novel calcium aluminateemelatonin scaffold enhances bone regeneration within a calvarial defect. J Pineal Res. 2012;53:206e18.
  26. Mahmood N., Jumma K. M., Hussain S. A. Dose-dependent anti-inflammatory activity of melatonin in experimental animal model of chronic inflammation. Global journal of pharmacology. 2010;4(2):66-70.
  27. Tekbas O. F., Ogur R., Korkmaz A., Kilic A., Reiter R. J. Melatonin as an antibiotic: new insights into the actions of this ubiquitous molecule. J Pineal Res. 2008;44:222e6.
  28. Boga J. A., Coto-Montes A., Rosales-Corral S. A., Tan D. X., Reiter R. J. Beneficial actions of melatonin in the management of viral infections: a new use for this “molecular handyman”? Rev Med Virol. 2012;22:323e38.
  29. Zhou W., Zhang X., Zhu C. L., He Z. Y., Liang J. P., Song Z. C.  Melatonin Receptor Agonists as the ªPerioceuticsº Agents for Periodontal Disease through Modulation of Porphyromonas gingivalis Virulence and Inflammatory Response. PLoS ONE. 2016;11(11):e0166442.
  30. Almughrabi O. M., Marzouk K. M., Hasanato R. M., Shafik S. S. Melatonin levels in periodontal health and disease. J Periodontal Res. 2013;48:315–321.
  31. Gómez-Moreno G., Cutando-Soriano A., Arana C., Galindo P., Bolaños J., Acuña-Castroviejo D., Wang H. L. Melatonin expression in periodontal disease. J Periodontal Res. 2007;42:536–540.
  32. Bertl K., Schoiber A., Haririan H., Laky M.,Steiner I., Rausch W. D .,Andrukhov O.,Rausch-Fan X. Non-surgical periodontal therapy influences salivary melatonin levels. Clin Oral Investig. 2013;17:1219–1225.
Share Button
(Visited 70 times, 1 visits today)

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.