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