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Table of Contents   
SYSTEMATIC REVIEW AND META-ANALYSIS  
Year : 2020  |  Volume : 31  |  Issue : 4  |  Page : 593-600
Role of melatonin in periodontal disease - A systematic review


Department of Periodontics, Saveetha Dental College, Saveetha University, Chennai, Tamil Nadu, India

Click here for correspondence address and email

Date of Submission14-Mar-2018
Date of Acceptance15-Aug-2019
Date of Web Publication16-Oct-2020
 

   Abstract 


Background and Aims: Melatonin is an indolamine that is primarily secreted by the pineal gland. It has immunomodulatory as well as antioxidant properties. It is a potent anti-oxidant that protects against inflammation and cellular damage caused by reactive oxygen species, also has potent angiogenic function that adds on to the benefits of melatonin. As a result of these actions, melatonin may be useful as an adjuvant in the treatment of various conditions in the oral cavity. The aim of this study is to systematically evaluate the role of melatonin in periodontal disease. Methods: An extensive review of the scientific literature was carried out using PubMed, Science Direct, Google Scholar and the Cochrane base. Research articles were collected upto December 2017. Results: Melatonin may have beneficial effects in certain inflammatory oral pathologies, mainly periodontal diseases where they inhibit bone resorption destroy reactive oxygen species, stimulates osteoblastic differentiation. Salivary melatonin could also act as a risk indicator for periodontal diseases. Conclusion: Many studies showed that the melatonin levels in GCF, Saliva, Serum of patients suffering from chronic periodontitis is lowered suggesting that may play a pivotal role in protecting the tissue from damage caused by oxidative stress. However, there exists no data on the concentration needed, method of application for potential benefits. Randomized clinical trials in this field are needed to fill the lacunae and better improve our understanding.

Keywords: Anti-oxidant, GCF, periodontitis, reactive oxygen species, risk indicator, salivary melatonin, serum melatonin

How to cite this article:
Meenakshi S S, Malaiappan S. Role of melatonin in periodontal disease - A systematic review. Indian J Dent Res 2020;31:593-600

How to cite this URL:
Meenakshi S S, Malaiappan S. Role of melatonin in periodontal disease - A systematic review. Indian J Dent Res [serial online] 2020 [cited 2020 Oct 31];31:593-600. Available from: https://www.ijdr.in/text.asp?2020/31/4/593/298400



   Introduction Top


Melatonin (N-acetyl-5-methoxy-tryptamine) is an indoleamine that is synthesized and secreted by the pineal gland and various other organs, like the retina, bone marrow, and intestines in a circadian pattern. Extra pineal sites do not contribute much to production of melatonin; they also need specific stimuli in order to secrete.[1] Melatonin was isolated and characterized in 1958.[2] Binding of the indoleamine to membrane receptors in all tissues mediates numerous physiological functions.[3],[4] Melatonin is able to enter the subcellular compartment due to its lipophilic properties thereby existing in high concentrations in the nucleus and the mitochondria of cells[5],[6] being capable of binding to some cytosolic proteins like kinase-C,[7] calmodulin[8] and calreticulin.[9] The mechanism of formation of melatonin in brief is that, free tryptophan from the blood is taken up by the pinealocytes and converted into serotonin, with the help of the enzymes tryptophan-5-hydroxylase and 5-hydroxytryptophan decarboxylase that successfully hydroxylate and decarboxylate tryptophan, respectively. During the night, by the action of N-acetyltransferase, serotonin is converted to N-acetylserotonin on which the enzyme hydroxyindole-O-methyl transferase acts on, causing its methylation, thereby forming melatonin. In animals including man, melatonin level reaches its maximum at the middle of the night and decreases to low levels during the day.[10] Because of the association of the synthesis of melatonin during night, it is referred to as the chemical expression of darkness.[11] Melatonin is not considered a hormone since it is synthesized in multiple organs and does not exert any effect on a specific target.[6] Melatonin production decreases with advancing age.[12] Since there are no morpho-physiological barriers to melatonin, it can rapidly cross the blood-brain barrier, the placenta, and all of the other potential cellular impediments.[13] Melatonin controls the circadian rhythms[14],[15] regulates body temperature,[16] regulates sexual development and the reproductive cycle, and activates the immune system.[17],[18] In the oral cavity, melatonin has paracrine effects on nearby cells;[19] also acts as an antioxidant and an anti-inflammatory agent and plays an essential role in bone formation and in the reduction of bone resorption and stimulates other antioxidative enzymes. It regulates the secretion of interleukin-2 (IL- 2) and interferon-alpha thereby playing an immunomodulatory role[17],[20] stimulates the proliferation and synthesis of type I collagen and promotes bone formation.[2] Once in the blood, melatonin also gets discharged into the saliva. 70% of plasma melatonin is bound to albumin and only a small portion of it is free-circulating melatonin.[7]

Aim of the review

To systematically evaluate the role of melatonin in periodontal disease.

Structured question

What is the role of melatonin in periodontal disease?

PICO Analysis

Population:Patients with chronic periodontitis, aggressive periodontitis

Intervention: (None) Since we have chosen observational as well as experimental trials.

Comparison: Healthy controls

Outcome: Levels of Salivary melatonin, Serum melatonin, GCF melatonin, improvement in clinical parameters


   Methods Top


A search was performed in electronic databases, such as PUBMED, Cochrane central register of controlled trials, google scholar, science direct using various search terms such as “chronic periodontitis” , “aggressive periodontitis” , “periodontoses” , “periodontal disease” , “melatonin” , “GCF melatonin” , “Serum melatonin” , “topical melatonin” . No limits and language restriction were applied during the electronic search to include all the possible clinical trials in the potential relevant article search phase of the systematic review [Figure 1] and [Figure 2].
Figure 1: PRISMA 2009 Flow Diagram

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Figure 2: Selection Flow Chart

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Selection criteria

Inclusion criteria

  • Studies related to expression of melatonin in periodontitis
  • Randomized control trials
  • Association studies
  • Case controlled studies
  • Cross sectional studies
  • In-vitro studies
  • Cohort studies


Exclusion criteria

  • Articles in other languages
  • Accepted but unpublished articles
  • Animal studies



   Results Top


Data extraction [Table 1] and [Table 2]
Table 1: Depicting the Results of the Various Studies

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Table 2: Depicting the results of various studies

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Periodontal disease is a chronic inflammatory disorder characterized by gingival ulceration and bleeding, apical migration of the junctional epithelium leading to periodontal pocket formation, and destruction of connective tissue attachment. An important aspect in periodontal disease is the generation of free radicals from oral bacteria and from the resultant inflammation.[21],[22] There is an increase in free radicals and a decrease in the antioxidant defence, which leads to an imbalance that causes substantial deterioration of the periodontal tissues.[23] Melatonin plays an important role in the control of periodontal disease due to its significant antioxidant property. The potential therapeutic effects of melatonin in periodontitis have been very well documented in various in vitro, animal studies and clinical trials.[24] But the relationship between periodontal status and the melatonin levels in saliva is still in conclusive.[25] Cutando et al.[26] measured the relationship between the salivary melatonin and the degree of periodontal disease in humans and found that there was an inverse correlation between the two; he further stated that as the severity of the periodontitis increases, the salivary melatonin level decreases, indicating that melatonin may play a protective role in prevention of progression of periodontitis. Similar findings were reported in another study by Almughrabi et al., in which authors compared the levels of salivary and the gingival crevicular fluid melatonin in four groups of patients with varying grades of periodontal disease, and found that the more severe the periodontitis, the lower the melatonin levels were, with significant differences between the healthy group, chronic, aggressive periodontitis groups.[27] They also reported that the melatonin levels in saliva and gingival crevicular fluid did not differ much. Gómez-Moreno et al.,[28] in their study found that the patients with periodontal disease had significantly lower plasma and salivary levels of melatonin, similar to the salivary/plasma melatonin ratio in healthy subjects. One study by Cutando et al. conducted on diabetic people, found that the salivary melatonin levels increased with the worsening of the periodontal status,[29] which contradicted the findings stated in other studies. The authors explained this increase to be a consequence of the oral inflammatory mediators. These low concentrations of melatonin found in saliva of patients with periodontal disease could be attributed to its free radical scavenging and anti-inflammatory property to combat the elevation in the levels of reactive oxygen species and inflammation found in these patients. In a study on ligature-induced periodontitis in rats by Kara et al., the treatment of these animals with melatonin seemed to alleviate gingival inflammation[30] and the authors further concluded stating that melatonin could decrease the oxidative stress and inflammation through down regulation of inflammatory cytokines. A cohort study by Kristina Bertl et al., showed that salivary melatonin levels were reduced in periodontitis group in comparison to healthy controls and their levels significantly improved following non-surgical periodontal therapy.[31] Several research studies by Lodhi et al., Ghallab et al. support the idea that melatonin could be useful as a biomarker to monitor the severity of periodontal disease,[32],[33] and could also be a possible treatment strategy to combat periodontitis.


   Discussion Top


The role of melatonin both in physiological and pathological processes related to periodontitis is basically due to its antioxidant and anti-inflammatory effects, as well as it acting as a mediator in bone formation and resorption.[34] Free radicals are highly reactive molecules with an unpaired electron in their valence shell. They are capable of causing damage to the adjacent molecules by abstracting an electron or donating it to them. The oxygen or nitrogen derived free radicals that generate reactive oxygen or nitrogen species (ROS and RNS), which are considered to be highly destructive are proven to be directly neutralized by Melatonin[35],[36],[37] acting due to its antioxidant properties and its ability to detoxify various free radicals, it can also block the reactive oxygen species produced by the superoxide dismutase,[38] thereby playing an important role in regulating the bone resorption process. Pharmacological doses of Melatonin also down regulates the receptor activator of nuclear factor -B ligand (RANKL)-mediated osteoclast formation and activation, osteoblast differentiation is that of mediator of angiogenesis,[39] which in turn increases bone formation.[40],[41],[42] It was observed that in human osteoblasts in vitro, melatonin could stimulate at micro molar concentrations, the proliferation and synthesis of collagen type I, other bone matrix proteins and bone markers (including alkaline phosphatase, osteopontin, and osteocalcin). It also reduces the osteoblast differentiation period from the usual 21 days to 12.[41],[42],[43],[44] Another study in rats showed that melatonin influences precursors of bone cells in the bone marrow and protects the bone cells from oxidative attacks.[45],[46] Melatonin also acts as a significant modulator of calcium metabolism, preventing osteoporosis and hypocalcaemia.[47] Melatonin increases VEGF expression, which is a potent angiogenic modulator by exerting a significant pro-angiogenic activity in tissues, including bone.[48] In another study, melatonin had a positive effect on monocytes, cytokines, and fibroblasts having an impact on angiogenesis, as well.[49] Studies by Takechi et al., 2008,[50] Calvo-Guirado et al., 2010[51] and Koyama et al. stated that Implants treated with melatonin showed greater volume of mineralized bone around them which could be attributed to the property of inhibition of bone resorption by melatonin.[40] The use of melatonin in implants enhances an earlier osseointegration in different animal models.[2],[50],[51],[52],[53],[54],[55],[56],[57] Melatonin produces higher levels of bone near the implant threads, which could possibly be due to the action of this molecule on the osteoblasts.[52] Melatonin could be used as a biomimetic agent during implant placement due to its positive effect in the osseointegration during the early stages of healing[2],[58] making healing more effective. In most of the studies by Cutando et al. and Tresguerres et al., the effect of melatonin was enhanced in the early phase after the implant placement, and less evident at later stages of the healing process.[2],[51],[52],[53],[54] Gibbs et al. observed that the circulating half-life of melatonin was approximately 23 min,[59] thus, few authors speculate on the usage of carriers in melatonin in order to release it gradually and increase the half-life in the tissues.[53] Periodontal diseases are the result of the bacteria and their byproducts on the host response and it has been suggested that biological mediators, such as melatonin, could contribute to the protection of the periodontal tissues.[60] The amount of melatonin in saliva and in gingival crevicular fluid seems to be lower in those suffering from periodontitis, indicating that it may play a protective role but further research is required to confirm this hypothesis. In addition to these, few studies showed that melatonin may inhibit PGE2 synthesis thereby modulating periodontal destruction, which in turn inhibits osteoclast differentiation.[61] Melatonin is used as a possible therapeutic agent in the treatment of malignancies, with significant effects against solid tumors, could be used as a palliative therapy to alleviate the side effects of chemotherapy.[62] In addition to the above discussed properties, melatonin proves to be capable of reducing progressive alveolar bone loss, for ridge augmentation procedures, regenerative periodontal therapy, regression of symptoms of herpes viral infection, local inflammatory lesions, and possible treatment for xerostomia and oral cancer.


   Conclusion Top


In conclusion, the potential use of melatonin in periodontal diseases, studied by several researchers showed favourable results. Currently there is no data suggesting the best route of administration and appropriate dosage of this molecule. Therefore, further research should be carried out in this aspect for better clinical reliability. In most of studies, the relationship between melatonin levels in saliva and crevicular fluid decreased with an increase in the severity of periodontal disease, but there are few studies that contemplate the same. There arises a need for randomized controlled clinical trials employing melatonin to understand this paradigm better.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Dr. S Swarna Meenakshi
Department of Periodontics, Saveetha Dental College, Saveetha University, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdr.IJDR_227_18

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