ROR in the oral cavity

archives of oral biology 56 (2011) 944–950

available at www.sciencedirect.com

journal homepage: http://www.elsevier.com/locate/aob

Review

A new perspective in Oral health: Potential importance and actions of melatonin receptors MT1, MT2, MT3, and RZR/ROR in the oral cavity Antonio Cutando a,*, Jose Aneiros-Ferna´ndez b, Antonio Lo´pez-Valverde e, Salvador Arias-Santiago c, Jose Aneiros-Cachaza b, Russel J. Reiter d a

Departamento de Estomatologı´a, Facultad de Odontologı´a, Universidad de Granada, Spain Departamento de Anatomia Patolo´gica, Hospital Clı´nico Universitario de Granada, Spain c Departamento de Dermatologia, Hospital Clı´nico Universita´rio de Granada, Spain d University of Texas Center, San Antonio, TX, USA e Facultad de Odontologı´a, Universidad de Salamanca, Spain b

article info

abstract

Article history:

Background: Melatonin is involved in many physiological processes in mammals, amongst

Accepted 8 March 2011

others; it is implicated in sleep–wake regulation. It has antioxidant and anti-inflammatory

Keywords:

various tumours. Additionally an abnormal melatonin rhythm may contribute to depression

Melatonin

and insomnia. The mechanisms of action of melatonin include the involvement of mem-

properties. It also acts as an immunomodulator, stimulates bone metabolism and inhibits

Pineal

brane receptors (MT1, MT2), cytosolic binding sites (MT3 and calmodulin), and nuclear

MT1

receptors of the RZR/ROR family. Melatonin also has receptor-independent activity and can

MT2

directly scavenge free radicals. The current review addresses the functions of melatonin in

MT3

the oral cavity in relation to its receptors.

RZR/ROR

Methods: An extensive search was conducted on the following scientific databases Pub Med,

Periodontal

Science Direct, ISI Web of Knowledge and Cochrane database in order to review all pertinent

Cancer oral cavity

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. # 2011 Elsevier Ltd. All rights reserved.

* Corresponding author at: Facultad de Odontologı´a, Universidad de Granada, Colegio Ma´ximo s/n, Campus de Cartuja, E-18071, Granada, Spain. Tel.: +34 958 249025; fax: +34 958 249653. E-mail address: [email protected] (A. Cutando). 0003–9969/$ – see front matter # 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.archoralbio.2011.03.004

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archives of oral biology 56 (2011) 944–950

Contents 1. 2. 3. 4. 5.

1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Melatonin mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detection of MT1 and MT2 expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Expression and function of MT1 AND MT2 receptors in relation to the oral cavity. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction

In a previous review article,1 the functional and applied aspects of melatonin were discussed. The present work highlights its role at molecular and receptor (MT1, MT2, and MT3) levels and its implication in oral health. The effects of melatonin (MLT) were first described in 1917,2 but it was not isolated or identified until 1958.3 Since that date, it has been found to have multiple important functions.4 MLT is predominantly synthesized and secreted by the pineal gland but it is also produced in other organs.5 Pinealocytes are responsible for MLT production through a sequence of wellknown reactions.6,7 It requires polysynaptic activation of Badrenergic receptors,8,9 which are indirectly regulated by neural stimulus from the suprachiasmatic nucleus (SCN).10,11 Information on light/dark environments is transmitted via the retinohypothalamic tract to the SCN. Thereafter, an electrical neural signal is transferred to the upper thoracic cord and superior cervical ganglia, after which it is conveyed by postganglionic sympathetic fibres to the pineal gland12 (Fig. 1). The postganglionic terminals release norepinephrine, which activates adrenergic receptors in the pinealocyte membrane. Pinealocytes take up tryptophan from the blood and convert it to serotonin by hydroxylation and decarboxylation. During the daily dark period, serotonin is converted into N-acetyl-serotonin by the enzyme N-acetyltransferase (AANAT); subsequently, N-acetyl-serotonin is methylated to form MLT by the enzyme hydroxyindole-O-methyltransferase. Once produced, MLT is quickly discharged into the capillary bed in the pineal gland and possibly directly into the cerebrospinal fluid of the third

Fig. 1 – Minor salival gland (labial): expression of MT1 receptor striated ducts (E), intercalated ducts (I) and weak in the mixed acinus (arrow).

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ventricle.13 MLT acts on the SCN to assist in the modulation of circadian rhythms, and it influences the function of virtually all cells in the body as well.14,15 The rhythmic production of MLT is a consequence of neural impulses from the biologic clock, i.e., the SCN of the hypothalamus. In healthy individuals, blood MLT levels are maximal at night (4–8 h after darkness onset) and minimal during the daytime.16,17 Circulating nocturnal levels of MLT are commonly 10–20 times higher than concentrations measured during the day.18,19 MLT mediates seasonal variations in reproductive cycles in photoperiodic mammals20 and influences numerous aspects of circadian rhythms through its binding to membrane receptors.21 Recent studies22,23 have shown the functions of MLT to be more complex and not solely related to circadian and circannual cycles, documenting an association of MLT with cellular organelles and an action independent of an interaction with receptors. MLT is generally classified as a hormone. However, it is a molecule with paracrine, autocrine and antioxidant actions24 that exerts diverse receptor-dependent and -independent actions; hence, the exclusive definition of MLT as a hormone appears inadequate.25 As mentioned above, MLT is produced in several organs, and likewise melatonin-forming enzymes are found in many tissues. Its production in the retina26 is well documented, and there is evidence of its synthesis in the ovary, lens, gastrointestinal tract and cells of the immune system,27 amongst others. Because it is highly lipophilic, MLT enters every cell in the organism. It is found in high concentrations in the bone marrow and intestine and, at the subcellular level, in the nucleus and mitochondria.28 After its release into the blood, MLT passively diffuses via the saliva and oral mucosa into the oral cavity.29,30 Salivary MLT concentrations are 15–33% of plasma concentrations. Around 70% of plasma MLT is bound to albumin and does not enter the saliva to any appreciable extent. Measurement of salivary MLT concentrations is a reliable technique to monitor circadian rhythms of the MLT and other processes in which indoleamines participate.29 Peripherally, MLT undergoes 6-hydroxylation in the liver followed by its conjugation primarily to sulphate.31 The resulting product, 6-hydroxymelatonin sulphate, is excreted in the urine as a major MLT metabolite. There is a larger amount of this product in urine at night than during the day, reflecting the pineal MLT synthesis and secretion cycle. MLT is also converted, presumably in all cells, to cyclic 3-hydroxymelatonin. This metabolite can also be detected in urine.32 In elderly humans, the amplitude of nocturnal pineal MLT product can be severely attenuated, although there appears to be significant inter-individual variations in the rate at which MLT is lost.33 The gradual waning of the synthetic capability of

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the pineal gland is probably related to multiple factors, including a reduction in the number of B-adrenergic receptors on pinealocyte membranes, deterioration of the melatonin, synthetic machinery within the pineal gland and a progressively weakening signal from the SCN.33 The beneficial effects of melatonin in herpes infection of the oral cavity have been compared with Acyclovir. In this case, melatonin proved beneficial in reducing the severity of herpes at least as effectively as the prescription drug. This is consistent with the actions of melatonin on other viral infections where it has also been found to reduce the severity of those infections. The benefits of melatonin in these situations seem to stem from the immunomodulatory actions of melatonin in the stimulation of IL-1B, which has antiviral effects. The suppressive actions of melatonin on herpes may also relate to its stimulation of NK, CD4 cells, etc. At this point, the precise mechanism whereby melatonin may reduce the severity of herpes infections remains unknown.34

2.

Melatonin mechanism of action

MLT performs its functions by means of various mechanisms. MLT and its metabolites function as direct scavengers of free radicals and as an indirect antioxidant35,37 and by interaction with intracellular proteins, e.g., calmodulin38 nuclear membrane receptors of the RZR/ROR family,39 and receptors located at the cell membrane, e.g., MT1 and MT2.40 MLT was discovered as a highly effective scavenger of free radicals and an efficient antioxidant more than a decade ago.41 It directly neutralizes a number of toxic oxygen- and nitrogenbased reactants, including the hydroxyl radical (OH), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), singlet oxygen (1O2), the peroxynitrite anion (ONOO ) and peroxynitrous acid (OHOOH).42,43 MLT also has indirect antioxidative actions, stimulating the synthesis of another important intracellular antioxidant, glutathione (GSH),44 and promoting its enzymatic recycling in cells to ensure it remains primarily in glutathione reduced form.45,46 Finally, MLT preserves the functional integrity of other antioxidative enzymes, including superoxide dismutases and catalase. MLT may also reduce free radical generation in mitochondria by improving oxidative phosphorylation, thereby lowering electron leakage and increasing ATP generation.47 Free radical damage has been implicated in a wide variety of diseases which are suppressed with the use of MLT in experimental models of many of these conditions,48,50 including: ischemia/reperfusion injury (in the brain, heart, gut, liver, lung, and urinary bladder), toxic drug exposure, bacterial toxin exposure, Schistosomiasis, heavy metal toxicity, amyloid b (Ab) protein exposure (as model of Alzheimer’s disease),51 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure (as model of Parkinsonism) and in Parkinson disease in humans.52–55 MLT has been successfully used as an adjuvant treatment in neonates with sepsis (a high free radical condition)56 and transient ischemia/reperfusion.57 MLT has also proven beneficial in skin erythema due to exposure to ultraviolet radiation,58 in iron and erythropoietin pathology,59 and tardive dyskinesia,60 which are all believed to involve free radical damage to essential macromolecules as part of the

destructive process. There is widespread agreement that MLT is a non-toxic molecule; hence, there are likely to be continuing reports of its use in humans to combat free radical damage. MLT also limits tissue damage induced by drugs whose toxicity is a consequence of free radical generation.61 MLT has been successfully used after radical oral surgery due to its antioxidative action and stimulatory and protective actions on intracellular enzymes involved in the repair process.62 Various studies have documented that MLT interacts with calmodulin, directly antagonising the binding of Ca2+ to this intracellular protein, which is involved in second messenger signal transduction.35 The putative antiproliferative effects of MLT on breast cancer cell proliferation may be partly mediated via this mechanism.63 The ability of MLT to inhibit nitric oxide synthase may also be a consequence of its interaction with calmodulin.64 Melatonin appears to be a natural ligand for the retinoidrelated orphan nuclear hormone receptor family (RZR/ROR). RZR/RORa is expressed in a variety of organs, whereas RZRb is specific for the brain and retina.65 The third member of the RZR/ ROR family, called RORg, is preferentially expressed in human skeletal muscle cDNA.66 MLT concurrently acts on nuclear receptors of the RZR/ROR family.67 It presumably regulates the immune system and circadian cycles via the nuclear receptor and these also may be involved in its regulation of antioxidative enzymes.68 The activation of these nuclear receptors by melatonin induces the repression of 5-lipooxygenase mRNA expression in human B cell lines.69 Also the regulation of IL-2 and IL-6 production by human mononuclear immune cells seems to be mediated through this mechanism.67,70 MLT also has a wide variety of functions via MT1 and MT2 membrane receptors, which are of particular interest in the present review. The first MLT receptors to be cloned were those located in the cell membrane, they were initially designated Mel1a and Mel1b.71,72 They were later classified by the International Union of Basic and Clinical Pharmacology (IUPHAR) as MT1 and MT2 receptors.73 MT1 and MT2 are members of a group of membrane receptors known as G-protein coupled receptors (GPCRs) that share a large part of their amino acid sequences.74 G-protein coupled receptor 50 (GPR50), also known as melatonin-related receptor (MRR), was cloned in 199675 and classified within the MT1 and MT2 subfamily of GPCRs due to its high affinity with the amino-acid-sequence that they share. Its function is not well known, but it appears to act as a receptor antagonist of the function of the MT1 receptor, whilst no relationship has been found between GPR50 and MT2. GPR50 has been implicated in some mental disorders (depression and bipolar disorders) and in lipid metabolism alterations.76 The recently discovered MT3 receptor is a cytosolic enzyme, quinone reductase (QR2).77 Calamini et al.78 identified the crystal structure of QR2 and compared it with that of MT3 and found they had an identical structure. However, not all authors support the proposition that MT3 receptor and QR2 is the same molecule.79

3.

Detection of MT1 and MT2 expression

In vivo studies of these receptors are complex and difficult. Amongst the few selective ligands described for them, some

archives of oral biology 56 (2011) 944–950

have agonist actions whilst others have antagonistic actions, with most showing a low affinity. The 4-phenyl-2-propionamidotetralin (4P-PDOT) ligand appears to be the most selective for research purposes. The paucity of ligands contributes to slow the progress related to knowledge on these receptors.80 Western blot, PCR and immunohistochemistry have been the most widely used techniques to detect MT1 and MT2 receptors in the organism. The few immunohistochemical studies published are largely on MT1,81 and there remains a need to establish staining patterns for these receptors.

4. Expression and function of MT1 AND MT2 receptors in relation to the oral cavity Using the above-mentioned techniques, an initial body map was created of the distribution of the expression of membrane receptors.82 Their expression was initially detected in the central nervous system83 and implicated in the pathophysiology of sleep.84,85 Their expression in the cardiovascular system may be related to myocardial contractility.86 They have been also detected in normal epithelial cells and in benign and malignant tumours in prostate and breast87 and in normal cells of the reproductive,88 gastrointestinal and hepatobiliary89 systems. In lamina propria of the oral mucosa, the receptors for MLT, especially MT1, have been detected in fibroblasts. Their expression has also been reported in melanoma and squamous cell carcinoma.90 Functional assays showed that melatonin can inhibit cell proliferation in cutaneous melanoma cells and in normal and malignant uveal melanocytes.91,92 Recent studies93,94 demonstrated that the MT1 receptor is expressed in normal mucosal cells, but not in cultured lines of squamous cell cancer lines, from the oral cavity. In vitro and in vivo studies in various tumour types have demonstrated that the presence of the MT1 and MLT treatment produces an inhibitory action on oral squamous cell carcinoma.93 MLT has a close functional relationship to the immune system, modulating its response to different types of diseases, including oral pathologies, e.g. periodontitis.1 Inhibition of MLT production by light or propanolol, a B-adrenergic receptor blocker, produces a suppression of the humoral and cellular response of the immune system.95 These observations can be extended to the oral cavity, since the presence of periodontal disease has been closely related to increased plasma and salivary MLT concentrations, enhanced cytokine production and a greater humoral and cellular response.96 MLT has an obvious positive action on bone. It inhibits osteoclastic action by preventing the binding of RANKL receptor at osteoblast level with RANK receptor at osteoclast level. The effect is to block osteoclastic proliferation and, hence, bone resorption whilst increasing the production of Osteoprotegerin (OPG) in the osteoblast. In normal situations, OPG blocks the binding of RANKL/RANK.97 This mechanism of MLT action may cause stimulation of bone formation around implant in the oral cavity.98 MT1 receptors have been detected in osteoblasts from healthy subjects.99 In relation to the diverse bone tumours that affect the oral cavity, there are not data on whether of these osseous tumours possess melatonin receptors, given that melatonin

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inhibits the growth of many tumours, their presence in the bone of the oral cavity may be advantage for the treatment of these conditions. In other parts of the organism, recent studies have demonstrated the presence of MT1-mRNA in both malignant and benign bone tumours. Detection of receptor in bone osteosarcomas, bone cysts and chondromas suggests the ability of MLT to act directly on bone cells. The presence of elevated levels of MT1 receptors in malignant bone tumours may be of prognostic relevance, since it is associated with a high degree of cell proliferation.101 The highest concentrations of MT1 melatonin receptors are found in young individuals,99 but no relationship has been found between their expression and age in studies of bone diseases. This suggests that the expression of MT1 in bone tumours may be regulated independently of the circulating MLT, perhaps due to local concentrations of this molecule. It has been suggested that the local production of MLT by the bone marrow may be a factor in tumour proliferation.100 An inverse relationship between MT1-mRNA and OPG-mRNA has been reported, with evidence of high expression of MT1-mRNA and low expression of OPG-mRNA in osteosarcoma cell lines and of elevated OPG-mRNA associated with low MT1-mRNA levels in normal human osteoblast cell lines. These data underline the importance of the MT1 receptor in bone disease.101 It is important therefore, to considerer studies on MLT and its receptors at level of the oral cavity in bone pathologies. Further research regarding role of melatonin in tooth development is still needed, although there is already work being done on this regard.102

5.

Conclusions

Contributions to the understanding of the location, structure and function of melatonin receptors have been important steps in the understanding of the cell biology of the ubiquitously acting indolamine, melatonin, the actions of which have been linked to many pathophysiologies. Currently, however, the importance of melatonin and its receptors in oral health and dentistry is less clear. The production of distribution maps, of membrane receptors in the oral cavity contribute to provide potential information about their significance for normal physiology, but there are also oral pathologies which express these receptors and their presence may indicate the severity of the process and, therefore, they have prognostic value. It is known that in certain pathologies, including, cancer, alcoholism, Alzheimer’s and other neurological disorders as well as in certain cardiovascular diseases, such as heart diseases, the use of MLT as a therapy leads to tangible improvements in these patients. In many of these situations, endogenous levels of MLT are depressed.103,104 The demonstration of low levels of MLT in diverse oral pathologies, would suggest possible new therapeutic strategies in which the use of this indoleamine may play an important role.30 MLT may be useful to treat disease of the oral cavity in patients with low concentrations of MLT but not where the tissues express MT1 and MT2 receptors. Melatonin is a known oncostatic agent. Interestingly, cancers such as breast, prostate, lung, gastric and colon

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cancer are accompanied by low plasma levels of MLT.105 The upregulation of MLT receptors in these tumours may have deficit of MLT. From the dental viewpoint, it is important to provide further experimental support for the essential functions of melatonin in the oral cavity. Preliminary evidence certainly suggests melatonin may have utility in the treatment of disease of the oral cavity. It is the hope of the authors that this review will provide a stimulus for further research related to physiological and pathophysiological actions of MLT in oral cavity. Funding: None. Conflict of interest statement: None declared. Ethical approval: Not required.

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