Melatonin: The potential avenues in dentistry

Antimicrobial properties

The Antimicrobial activity of melatonin has been demonstrated against a variety of microorganisms, including viruses, fungi, bacteria, and parasites. Through a variety of ways, including the disruption of cell membranes, interference with DNA replication, and modulation of immune responses to improve the body’s ability to fight infections, it can directly restrict the development and replication of these pathogens. Furthermore, by lowering oxidative stress, which can impair microbial defenses, the antioxidant properties of melatonin enhance antibacterial effectiveness. Strong anti-infection characteristics were also observed for the natural hormone melatonin. in vitro studies have shown that melatonin can hinder the growth of Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.⁷ Methicillin-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus have been demonstrated to be prevented by melatonin in in vitro experiments. The antibacterial effect of this hormone is often associated with immune responses that reduce the production of inflammatory cytokines and accelerate healing of bacterial lesions. For instance, melatonin and its receptor agonist ramelteon have antibacterial actions on planktonic-cultured P. gingivalis. Therefore they disrupt already-formed biofilms, prevent P. gingivalis biofilm growth, and lower P. gingivalis biofilm survival rates. It seems reasonable to assume that melatonin, which has potent antibacterial properties, also has anti-infection effects against oral pathogens, such as Aggregatibacter actinomycetemcomitans and Tannerella forsythia.⁸ Further research is required to confirm these findings. Although studies in this field are still underway, melatonin appears to have potential as a natural remedy for preventing infections and boosting immune system function.

Anti-inflammation properties

In addition to its role in sleep regulation, melatonin also has anti-inflammatory effects. By preventing the synthesis of pro-inflammatory cytokines and increasing the activity of anti-inflammatory molecules, it can modify a variety of immune responses and reduce inflammation. Melatonin also scavenges free radicals that fuel inflammation by acting as an antioxidant. Although encouraging, further studies are required to completely understand the scope and underlying mechanisms of the anti-inflammatory effects of melatonin.

Improved inflammation control may greatly lower the risk of tissue loss, because the abundance of inflammatory responses is a major cause of periodontal degeneration. Aspirin, NSAIDs, and corticosteroids are anti-inflammatory drugs that are known to cause serious side effects, such as bone issues. Melatonin has been shown to have powerful anti-inflammatory effects with no negative side effects.⁹ This hormone can prevent periodontal tissue damage by regulating inflammatory reactions. Additionally, it showed elevated levels of pro-inflammatory cytokines, a high receptor activator of the nuclear factor kappa beta/Osteoprotegerin ratio, and TLR4/MyD88 activity. Notably, melatonin substantially reduced TLR4/MyD88-mediated pro-inflammatory cytokine production to restore normal RANKL/OPG signalling. Kara et al. showed that melatonin reduces periodontal tissue loss and inflammatory cytokines (IL-1 and TNF-) in rats with periodontitis.¹⁰ Melatonin may also inhibit IL-1-stimulated TIMP-1, MMP-1, and CXCL-10 synthesis in human periodontal ligament cells.

Antioxidant properties

Melatonin is believed to have been generated between 3.0 and 2.5 billion years ago to aid in the neutralisation of toxic O₂ during photosynthesis by photosynthetic bacteria.¹¹ Although the original antioxidant function of melatonin has been preserved after more than three billion years of evolution, its other functions have significantly increased. Melatonin is widely acknowledged for its potent antioxidant and free radical-scavenging properties. Unlike most conventional antioxidants, melatonin metabolites can also neutralize oxygen derivatives. Because of this cascade reaction, this hormone is far more effective than other antioxidants, including glutathione, NADH, vitamin C, and vitamin E.¹²

Much work has been undertaken to reduce extreme ROS in periodontal tissue as a result of improved understanding of ROS’s impact of ROS on tissue deterioration. Melatonin may be a good choice because it is the strongest antioxidant. According to a randomized controlled clinical study, melatonin considerably lowered the levels of MMP-9 in GCF and boosted antioxidant capacity (TAC).¹³ In comparison with Non-Surgical Periodontal Therapy (NSPT) alone, NSPT combined with melatonin significantly reduced periodontal pocket depths in individuals with periodontitis and diabetes, according to a meta-analysis of two Randomized Controlled Trials. The delivery of DL-buthionine sulfoximine (BSO) and glutamate (GLUT) to Wistar rat gingival fibroblasts causes the creation of superoxide anions and cell loss, which are entirely stopped by melatonin. Additionally, it showed elevated levels of pro-inflammatory cytokines, a high receptor activator of the nuclear factor kappa beta/Osteoprotegerin ratio, and TLR4/MyD88 activity. Notably, melatonin substantially reduced TLR4/MyD88-mediated pro-inflammatory cytokine production to restore normal RANKL/OPG signalling. Melatonin may also inhibit IL-1-induced MMP-1,TIMP-1, and CXCL-10 synthesis in human periodontal ligament cells.¹⁴

Effects on bone protection

The most severe effects of periodontitis include bone resorption and tooth loss. Melatonin has been shown to have a positive effect on bone repair in various ways. For instance, melatonin accelerates the production and rate of type I collagen production in human bone cells and human osteoblastic cell lines. It also activates sirtuin 1, which stimulates osteogenic differentiation in bone marrow mesenchymal stem cells and inhibits adipogenesis while enhancing osteogenesis in human mesenchymal stem cells.¹⁵ Additionally, melatonin inhibits RANKL-induced osteoclastogenesis, which prevents bone resorption. Additionally, melatonin may shield the bone in the mouth. Melatonin inhibits IL-1, RANK, and RANKL expression levels while increasing OPG expression levels in rats with investigational periapical lesions to exert bone-protective and anti-inflammatory effects. Melatonin also drastically lowered the bacterial localization scores in periodontal tissues. Melatonin can promote the osteogenic development of dental pulp mesenchymal stem cells (DPSCs), and DPSCs preconditioned with melatonin can repair bone lesions in vivo. Activation of myeloperoxidase and alveolar bone resorption, and statistically, melatonin reduced RANKL and osteoclast activity. In addition, it protects osteoblasts from drug-induced damage caused by drugs. For example, the use of chlorhexidine causes MC3T3 cells to have poor morphology, elevated levels of total ROS and superoxide, and decreased numbers of osteoblasts that are metabolically and physiologically active.¹⁶ Notably, melatonin can mitigate the damage caused by chlorhexidine in MC3T3 cells, safeguarding osteoblasts during chlorhexidine treatment. Additionally, melatonin may be useful for the treatment of peri-implantitis. In the lipopolysaccharide-induced peri-implantitis rat model, melatonin reduced the incidence of peri-implantitis by lowering the number of osteoclasts, decreasing the generation of pro-inflammatory cytokines, and limiting harm to the alveolar bone.¹⁷

Impact on bone regeneration

Melatonin enhances osteoblast development and promotes bone formation, as is widely known. Melatonin has been shown to increase the expression of genes such as osteocalcin and alkaline phosphatase, which are involved in bone mineralization. This encourages the creation of structurally sound bone tissue by causing the accumulation of calcium and other minerals in the bone matrix. The immunomodulatory, antioxidant, and anti-inflammatory properties of melatonin may increase its osteoconductive effects. The cells responsible for bone resorption, osteoclasts, have been shown to be suppressed by melatonin. Melatonin inhibits osteoclast activity, which is essential for effective bone regeneration, maintaining bone mass, and preventing excessive bone loss.

Bone graft materials and bioactive scaffolds are utilized to promote the redevelopment of bone that has vanished because of periodontal infection or tooth loss.¹⁸ When exposed to calcium aluminate scaffolds that also contain platelet-rich plasma and melatonin, human osteoblasts has been observed to multiply. Melatonin-based scaffolds have potential for guided tissue regeneration in the future.

Melatonin and dental implants’ osseointegration

Osseointegration is the process by which a dental implant combines with the surrounding bone, and its influence on this process has been studied. Melatonin has been shown to facilitate angiogenesis and formation of new blood vessels, which are essential for supplying oxygen and nutrients to the implant site throughout the healing process.¹⁹ Enhanced blood flow can facilitate osseointegration of dental implants and accelerate tissue recovery. Dental implants must have their surfaces altered before being placed into the periodontal bone to optimize their bioactivity. Ion leakage, leftover particles, and bioactive coating delamination are some of the drawbacks of modified implants. Unstable implant coatings can be successfully replaced by melatonin. Interthread bone development and mineralization were much higher at implant sites treated with melatonin powder than at the control implant sites. The osteogenic outcomes of porcine bone grafts in calcium-coated titanium dental implants were enhanced by melatonin. Moreover, the effects of melatonin on implant sites in vivo appeared to be enhanced when combined with growth hormone. Fibroblast growth factor-2 and melatonin injections have been found to increase the amount of bone in contact with zirconia and titanium implants. However, more extensive studies in both animals and humans are necessary to fully understand how melatonin affects the ability of implants to promote bone growth. According to Gomez-Moreno et al. (2015), the bone development surrounding implants benefits from the action of melatonin.²⁰

Additionally useful in the battle against peri-implantitis, melatonin suppresses the generation of pro-inflammatory cytokines, lowers production of osteoclasts thereby reducing bone resorption.²¹ In vitro, melatonin stimulates osteoblastic growth and activity, while inhibiting osteoclastic formation and activity. Melatonin is also used in radiation therapy as it lowers oxidative stress in the hard and soft tissues of the oral cavity. It also increases the longevity of periodontal ligament cells by modulating autophagy. Furthermore, melatonin affects how The body reacts to stress, particularly the stress induced by surgical operations such as implant installation. Melatonin may help osseointegration indirectly by lowering stress-related variables that might obstruct the healing process. Recent studies have investigated the possible influence of melatonin on dental implant osseointegration, that is, the integration of the implant with the surrounding bone.

Use of melatonin to decrease the cytotoxicity of medications and dental products

Several drugs affect the periodontium. Proksch et al. found that melatonin decreased the levels of reactive oxidant species and the cytotoxic effects of generally utilized oral antiseptic medicines such as chlorhexidine.²² In addition, it shields periodontal cells from bisphosphonate necrosis. To avoid osteonecrosis of the jaw caused by bisphosphonates, topical melatonin therapy should be used before dental surgery, and methacrylate chemicals, which are known to have cytotoxic effects, are present in common dental polymers. Because of its antioxidant properties, melatonin has been proven to shield dental pulp cells, in contrast to DNA destruction caused by methacrylate. Thus, when used as gel mouthwashes, sublingual tablets, or gels, melatonin can reduce the genotoxic effects of dental materials created by methacrylates.

Melatonin’s impact on oral carcinoma

Studies have been conducted on the effects of melatonin on oral carcinoma and mouth cancer. Although there is some evidence to support its potential benefits in the prevention and treatment of oral cancer, further research is necessary to fully understand its effects. Studies have shown that they possess anticancer properties, including pro-apoptotic, antimetastatic, and antiproliferative effects. These qualities can help stop the growth and metastasis of oral cancer cells. Since Reactive Oxygen Species are involved in the development of precancerous lesions, such as lichen planus and leukoplakia, the antioxidant properties of melatonin aid in the prevention or treatment of oral cancer. It can alter the immune system, boosting the activity of immune cells that are engaged in immunological defense and cancer surveillance. This immunosuppressive action could help the body to identify and eliminate oral cancer cells. Additionally, radiation therapy, which is frequently used to treat oral cancer, protects against melatonin-protected healthy tissues. Its radioprotective properties, when combined with radiation treatment, have been studied. This could increase the vulnerability of cancer cells to radiation-induced cell death while shielding healthy oral tissues from the harmful effects of radiation.

According to recent in vitro studies, melatonin may stop the progression of oral cancer by blocking the activation of metalloproteinase-9. Therefore, melatonin-containing toothpastes, gels, and rinses may aid in the prevention and slowing of oral cancers.¹⁵

Therefore, further studies, including clinical trials, are required to completely clarify the effectiveness, appropriate dose, and safety profile of melatonin in the context of treating and preventing oral cancer, even though preliminary evidence points to a possible significance for the hormone in this regard. Melatonin should also be considered in conjunction with other proven treatments and lifestyle changes as a part of an all-encompassing strategy for the prevention and treatment of oral cancer.