Antonio Cutando

Melatonin in diseases of the oral cavity

BACKGROUND Melatonin is the principal secretory product of the pineal gland. It has immunomodulatory and antioxidant activities, stimulates the proliferation of collagen and osseous tissue and acts as a protector against cellular degeneration associated with aging and toxin exposure. Arising out of its antioxidant actions, melatonin protects against inflammatory processes and cellular damage caused by the toxic derivates of oxygen. As a result of these actions, melatonin may be useful as a co-adjuvant in the treatment of certain conditions of the oral cavity. METHODS An extensive review of the scientific literature was carried out using PubMed, Science Direct, ISI Web of Knowledge and the Cochrane base. RESULTS Melatonin, which is released into the saliva, may have important implications for oral diseases. Melatonin may have beneficial effects in certain oral pathologies including periodontal diseases, herpes viral infections and Candida, local inflammatory rocesses, xerostomia, oral ulcers and oral cancer. CONCLUSIONS Melatonin may play a role in protecting the oral cavity from tissue damage caused by oxidative stress. The experimental evidence suggests that melatonin may have utility in the treatment of several common diseases of the oral cavity. However, more specific studies are necessary to extend the therapeutic possibilities to other oral diseases.

Melatonin stimulates osteointegration of dental implants.

Abstract:  The aim of this study was to evaluate the effect of the topical application of melatonin on osteointegration of dental implants in Beagle dogs 14 days after their insertion. In preparation for subsequent insertion of dental implants, upper and lower premolars and molars were extracted from 12 Beagle dogs. Each mandible received cylindrical screw implants of 3.25 mm in diameter and 10 mm in length. The implants were randomly assigned to the mesial and distal sites on each side of the mandible. Prior to implanting, 1.2 mg lyophylized powdered melatonin was applied to one bone hole at each side of the mandible. None was applied at the control sites. Eight histological sections per implant were obtained for histomorphometric studies. After a 2‐wk treatment period, melatonin significantly increased the perimeter of bone that was in direct contact with the treated implants (P < 0.0001), bone density (P < 0.0001), new bone formation (P < 0.0001) and inter‐thread bone (P < 0.05) in comparison with control implants. Topical application of melatonin may act as a biomimetic agent in the placement of endo‐osseous dental implants.

Relationship between salivary melatonin levels and periodontal status in diabetic patients.

Abstract: Among other functions, melatonin exerts both antioxidative and immunoregulatory roles. The indoleamine is secreted in the saliva, although its role into the mouth is not known. Diabetic patients frequently display oral cavity pathologies such as periodontal disease (PD), an inflammatory disease coursing with an increase in free radical production. Thus, we compared the degree of PD and interleukin‐2 (IL‐2) levels with melatonin concentrations in plasma and saliva of diabetic patients. A total of 43 diabetic patients (20 with type I and 23 with type II diabetes) and 20 age‐ and sex‐matched controls were studied. Dental and medical history of all patients was in accordance with the criteria of the WHO. The periodontal status was evaluated by the Community Periodontal Index (CPI). Plasma and salivary melatonin levels were determined by specific commercial radioimmunoassays, and plasma IL‐2 was measured using a commercial enzyme‐linked immunosorbent assay kit. Diabetic patients had plasma and saliva melatonin levels of 8.98 ± 7.14 and 2.70 ± 2.04 pg/mL, respectively. These values were significantly lower (P < 0.001) than those obtained in plasma and saliva of controls (14.91 ± 4.75 and 4.35 ± 0.98 pg/mL, respectively). Plasma and salivary melatonin concentrations show a biphasic response in diabetic patients. Melatonin decreased in patients with a CPI index of 2, and then increased reaching highest levels in patients with a CPI index of 4. By contrast, IL‐2 levels decreased from CPI index 1 to 4. The results indicate that, in diabetic patients, the presence of a marked impairment of the oral status, as assessed by the CPI index, is accompanied by an increase in plasma and salivary melatonin. The increase in salivary melatonin excretion may have a periodontal protective role.

Melatonin plus porcine bone on discrete calcium deposit implant surface stimulates osteointegration in dental implants

Abstract:  The aim of this study was to evaluate the effect of the topical application of melatonin mixed with collagenized porcine bone to accelerate the osteointegration on the rough discrete calcium deposit (DCD) surface implants in Beagle dogs 3 months after their insertion. In preparation for subsequent insertion of dental implants, lower premolars and molars were extracted from 12 Beagle dogs. Each mandible received three parallel wall implants with discrete calcium deposit (DCD) surface of 4 mm in diameter and 10 mm in length. The implants were randomly assigned to the distal sites on each side of the mandible in three groups: group I implants alone, group II implants with melatonin and group III implants with melatonin and porcine bone. Prior to implanting, 5 mg lyophylized powdered melatonin was applied to one bone hole at each side of the mandible. None was applied at the control sites. Ten histological sections per implant were obtained for histomorphometric studies. After a 4‐wk treatment period, melatonin significantly increased the perimeter of bone that was in direct contact with the treated implants (P < 0.0001), bone density (P < 0.0001), new bone formation (P < 0.0001) in comparison with control implants. Topical application of melatonin on DCD surface may act as a biomimetic agent in the placement of endo‐osseous dental implants and enhance the osteointegration. Melatonin combined with porcine bone on DCD implants reveals more bone to implant contact at 12 wk (84.5 ± 1.5%) compared with melatonin treated (75.1 ± 1.4%) and nonmelatonin treated surface implants (64 ± 1.4%).

A new perspective in Oral health: Potential importance and actions of melatonin receptors MT1, MT2, MT3, and RZR/ROR in the oral cavity

BACKGROUND Melatonin is involved in many physiological processes in mammals, amongst others; it is implicated in sleep-wake regulation. It has antioxidant and anti-inflammatory properties. It also acts as an immunomodulator, stimulates bone metabolism and inhibits various tumours. Additionally an abnormal melatonin rhythm may contribute to depression and insomnia. The mechanisms of action of melatonin include the involvement of membrane receptors (MT1, MT2), cytosolic binding sites (MT3 and calmodulin), and nuclear receptors of the RZR/ROR family. Melatonin also has receptor-independent activity and can directly scavenge free radicals. The current review addresses the functions of melatonin in the oral cavity in relation to its receptors. METHODS An extensive search was conducted on the following scientific databases Pub Med, Science Direct, ISI Web of Knowledge and Cochrane database in order to review all pertinent literature. RESULTS Melatonin from the blood into the saliva may play an important role in suppressing oral diseases. It may have beneficial effects in periodontal disease, herpes and oral cancer, amongst others. CONCLUSIONS Melatonin contributes to protecting of oral cavity from tissue damage due to its action of different receptors. From the reviewed literature it is concluded that experimental evidence suggests that melatonin can be useful in treating several common diseases of the oral cavity. Specific studies are necessary to extend the therapeutic possibilities of melatonin to other oral diseases.

Melatonin and cancer: current knowledge and its application to oral cavity tumours

BACKGROUND Melatonin (MLT) is a molecule secreted by the pineal gland in cyclical periods. In mammals, MLT is involved in physiological processes, such as sleep/wake regulation in the circadian cycle. It has antioxidant and anti-inflammatory properties, functions as an immunomodulator, and stimulates bone metabolism. MLT is also involved in tumour processes in breast, prostate, liver, and bone cancers, among others, and in oral cavity tumours like epidermoid carcinoma. We are gradually increasing our knowledge of the underlying mechanism of MLT action in the aforementioned tumour processes, in which MT1, MT2, MT3, and RZR receptors appear to play a highly important role. These receptors belong to a large family of G-protein-coupled transmembrane receptors, some of which have been linked to melatonins anticancer action, to tumour growth, and to prognosis. The objective of this article is to provide a clear review of research into the range of MLT functions, focusing specifically on MT receptors. We aim to contribute interesting, new approaches to research into oral cavity tumours. METHODS An extensive review of the research literature was conducted using PubMed, Science Direct, ISI Web of Knowledge, and the Cochrane base. RESULTS This study highlights the growing importance of MLT in the prognosis and treatment of certain tumours, including epidermoid carcinoma in the oral cavity. Moreover, it opens up a highly original, encouraging line of research in the field of tumours. CONCLUSIONS MLT contributes to protecting the oral cavity from tissue damage caused by receptor action. Experimental evidence suggests that it may be useful in the treatment and prognosis of tumour processes in the oral cavity.

Topical Application of Melatonin and Growth Hormone Accelerates Bone Healing around Dental Implants in Dogs

BACKGROUND Growth hormone (GH) and melatonin belong to the group of growth factors. These substances have been proposed to improve and accelerate osseous healing using topical applications. PURPOSE The aim of this study was to evaluate the effect of the topical administration of GH and melatonin on osseointegration of dental implants in Beagle dogs 2, 5, and 8 weeks after their insertion. MATERIALS AND METHODS Twelve adult Beagle dogs and 48 implants were used in the study. The maxillary and mandibular premolars and molars were extracted. Each mandible received cylindrical screw implants of 3.25 mm in diameter and 10 mm in length. Prior to implanting, 4 IU of recombinant human GH and 1.2 mg of lyophilized powdered melatonin was applied to one osteotomy at each side of the mandible. None was applied at the control sites. The implants were retrieved at 2, 5, and 8 weeks for light microscopic examination, energy-dispersive x-ray microanalysis, and histomorphometric measurements in ground sections. RESULTS At week 2, BIC was significantly higher in the melatonin-growth hormone group than in the implant control one (34.20 vs 25.05%; p = .010). The M-GH group also increased significantly the peri-implant bone area (64.72 vs 53.20%; p = .038) and interthread bone area (35.62 vs 25.08%; p = .02). At weeks 5 and 8, BIC and bone density around implants were similar to both groups. Significant differences were detected in bone neoformation at 8 weeks in ML-GH group (9.04 vs 7.53%; p = .05). Regarding the mineral composition, in ML-GH group increments in concentrations of phosphorus (10.70 vs 10.34; p = .013) were observed at 2 weeks and of magnesium (0.29 vs 0.25; p = .019) 5 weeks after implantation. CONCLUSION The present study confirms that GH and melatonin synergistically enhance new bone formation around titanium implants in early stages of healing.

Evaluation of Effects of Topic Melatonin on Implant Surface at 5 and 8 Weeks in Beagle Dogs

PURPOSE The aim of this study was to evaluate the effect of the topical application of melatonin on osteointegration of dental implants in Beagle dogs 5 and 8 weeks after their insertion. MATERIALS AND METHODS For subsequent insertion of dental implants, upper and lower premolars and molars were extracted from 12 Beagle dogs. Each mandible received cylindrical screw implants of 3.25 mm in diameter and 10 mm in length. The implants were randomly assigned to the mesial and distal sites on each side of the mandible. Prior to implanting, 1.2 mg lyophylized powder melatonin was applied to one bone hole at each side of the mandible. None was applied at the control sites. Eight histological sections per implant were obtained for histomorphometric studies. RESULTS After 5- and 8-week treatment periods, melatonin significantly increased the inter-thread bone (p < 0.05) and new bone formation (p < 0.05) in comparison to control implants in both weeks. There were no significant increases in the bone-to-implant contact and peri-implant bone (p > 0.05). CONCLUSION Topical application of melatonin may act as a biomimetic agent in the placement of endo-osseous dental implants at 5 and 8 weeks after the implantation.

Melatonin reduces oxidative stress because of tooth removal

Previous studies have reported that oral inflammatory processes, such as periodontitis, can trigger signals to increase not only plasma melatonin levels, but also melatonin levels in the oral cavity, where indoleamine may have an antioxidant effects. The direct action of melatonin as a free radical scavenger of both reactive oxygen (ROS) and reactive nitrogen species (RNS) [1] is complemented by an indirect stimulatory effect on antioxidant enzymes, including glutathione peroxidase (GPx) and reductase (GRd), superoxide dismutase, and catalase [2]. Because of GRd stimulation, melatonin favors the recycling of glutathione (GSH) from glutathione disulfide (GSSG), maintaining a high GSH/GSSG ratio. Melatonin also promotes the de novo synthesis of GSH by stimulating the activity of c-glutamyl-cysteine synthetase. But melatonin is also capable of reducing nitric oxide (NO) and the peroxynitrite anion (ONOO ) generation because of its ability to inhibit iNOS activity and expression which increase as a consequence of inflammation [3]. Melatonin may also play an immunoenhancing role in the mouth, as patients with poorer periodontal status, exhibiting bone damage and gingival involvement, show concomitant high IL-2 and melatonin levels, which may stimulate CD-4 lymphocytes in response to periodontal disease [4]. It is now well established that the acute inflammatory response of gingival tissue during the first 24–48 postextraction hours causes an intense polymorphonuclear neutrophil infiltration, which is responsible for the increase in ROS and RNS production [5]. Thus, the aim of this study was to ascertain whether plasma reflects the acute inflammatory response as a result of tooth extractions in Beagle dogs, and whether melatonin treatment can prevent it. Maxillary and mandibular premolars and molars of eight Beagle dogs were removed under general anesthesia. After the tooth extractions and before suturing, four dogs received local melatonin (2 mg) applied in extraction wounds and gingival tissue surrounding the premolar and molar area. Measurements were made 24 hr later [6]. The findings are summarized in Table 1. Research into inflammatory processes in the oral cavity, such as periodontitis, has demonstrated the involvement of oxidative stress. One day after oral surgery, the group of dogs that did not receivemelatonin presented a significant increase in oxidative stress in plasma as a consequence of the subsequent inflammatory process. Besides the inflammatory processes, other mechanisms, such as severing of gingival fibers, damage to periodontal vessels, and mechanical aggression to oral tissues, also contribute to oral damage after tooth removal [7]. Together, these events may provoke increased oxidative stress. In turn, increased ROS stimulate the production of pro-inflammatory cytokines, transcription factors and vascular cell adhesion molecules, increasing the severity of the inflammatory process and the synthesis of RNS, such as NO and ONOO – [5]. Both ROS andRNS locally generated in the oral cavity after tooth removal may pass to the blood stream. In this study, plasma levels of LPO and of NOx, which indicate increased ROS and RNS production, respectively, were significantly higher 24 hr after oral surgery. Overproduction of lipid hydroperoxides and aldehyde compounds can cause depletion of GSH, disrupting mucosal turnover [8]. Our results further confirmed these observations, as GSSG levels and the GSSG/GSH ratio were significantly higher in the untreated group. The increased GPx activity observed after tooth extraction probably reflects the activation of antioxidant processes. However, the increased GSSG produced in these circumstances could not efficiently be reduced to GSH because of the barely perceptible increase in GRd activity. The application of melatonin into the alveolar sockets resulting from tooth removal caused a statistically significant reduction in oxidative stress in blood. Increased levels of LPO following tooth removal were counteracted by melatonin 24 hr after surgery. Our findings support those of other studies that have demonstrated that in vivo melatonin efficiently limits the peroxidation of lipids [1, 3, 9]. It may be that melatonin achieves this high degree of lipid protection by interfering with the radicals that initiate the peroxidation process, mainly the hydroxyl radical (HO) and ONOO , and by positioning itself among the membrane lipids in such a way as to impede the oxidation of the polyunsaturated fatty acids [10]. Treatment with melatonin also counteracted NOx levels increased after oral surgery, reducing their concentrations below those of the control group. The inhibition of iNOS by melatonin application might be responsible for the reduction in NOx, by diminishing gingival damage and postextraction oxidative stress in the oral cavity. Additionally, melatonin might also decrease nitrosative stress in gingival cells by directly neutralizing ONOO . In addition to reducing plasma markers of oxidative (LPO) and nitrosative (NOx) damage, melatonin also significantly lowered the GSSG/GSH ratio, the best index of intracellular oxidative damage in red blood cells. Besides its direct antioxidant role, which reduces GSH consumption, melatonin treatment also promoted GRd activity, which may account for the reduction of GSSG and for the increase in GSH levels, which may provide the cell with an extra amount of GSH [11]. Besides protecting GRd from oxidative damage, the effect of melatonin on GRd activity also may depend on a genomic effect of indoleamine in increasing the expression of the enzyme [12, 13]. Regulation of the GSH redox cycling system might be of great significance for oral tissue homeostasis, as GSH J. Pineal Res. 2007; 42:419–420

Denture stomatitis: Quantification of interleukin-2 production by mononuclear blood cells cultured with Candida albicans

Denture stomatitis is usually associated with the presence of yeast, particularly Candida albicans, and several bacteria. In this study mononuclear blood cells were grown in the presence of Candida albicans from a single colony, and interleukin-2 production induced in T lymphocytes was measured. Blood cells were from a population of patients with denture stomatitis and a control group of denture wearers without stomatitis. Induction of interleukin-2 production was correlated with factors that condition denture stomatitis, namely, isolation of Candida albicans in selective medium, age of the denture, and diabetes. Concentrations of interleukin-2 in supernatant and serum were also compared. Significant differences in interleukin-2 production were found between patients with denture stomatitis and controls. Statistical analysis demonstrated a significant association between isolation of Candida albicans and elevated interleukin-2 production in cultures from patients with and without denture stomatitis.