World J Gastroenterol. 2011 September 14; 17(34): 3888-3898.
Published online 2011 September 14. doi: 10.3748/wjg.v17.i34.3888.
Distribution, function and physiological role of melatonin in the lower gut
Chun-Qiu Chen, Jakub Fichna, Mohammad Bashashati, Yong-Yu Li and Martin Storr.
Chun-Qiu Chen, Department of Gastrointestinal Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 200072 Shanghai, China
Chun-Qiu Chen, Jakub Fichna, Mohammad Bashashati, Martin Storr, Division of Gastroenterology, Department of Medicine, University of Calgary, 3330 Hospital Dr NW, T2N 0N1 Calgary, Alberta, Canada
Yong-Yu Li, Department of Pathophysiology, Tongji University School of Medicine, 200092 Shanghai, China
Martin Storr, Division of Gastroenterology, Department of Medicine, University of Munich, Marchioninistr 15, 81377 Munich, Germany
Author contributions: Storr M designed the project; Chen CQ, Fichna J, Bashashati M and Li YY performed literature research; Chen CQ, Fichna J, Bashashati M and Storr M wrote the paper.
Correspondence to: Martin Storr, MD, Division of Gastroenterology, Department of Medicine, University of Munich, Marchioninistr 15, 81377 Munich, Germany. gidoc@gmx.com
Telephone: +49-89-70950 Fax: +49-3212-1027208
Received January 11, 2011; Revised March 18, 2011; Accepted March 25, 2011;
Abstract
Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. Melatonin exerts its physiological effects through specific membrane receptors, named melatonin-1 receptor (MT1), MT2 and MT3. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies. Stable levels of melatonin in the lower gut that are unchanged following a pinealectomy suggest local synthesis and, furthermore, implicate physiological importance of endogenous melatonin in the GI tract. Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. These human studies include patients with lower GI diseases, especially patients with irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. In this review, we summarize the presently available information on melatonin effects in the lower gut and discuss available in vitro and in vivo data. We furthermore aim to evaluate whether melatonin may be useful in future treatment of symptoms or diseases involving the lower gut.
Keywords: Melatonin, Ileum, Colon, Receptor, Motility, Inflammatory bowel disease, Clinical trial
INTRODUCTION
Melatonin (N-acetyl-5-methoxytryptamine), discovered in 1917, is found in humans, animals, plants and microbes. It is a lipophilic compound diffusing rapidly through biological membranes and is involved in many regulatory processes, such as biological rhythms, intestinal reflexes, protection against inflammation, metabolism and reproduction. Additionally, melatonin may act as a mediator of inter-organ communication, e.g., between gut and liver[1].
In animals, melatonin was first reported in the bovine pineal gland in the year 1958, and in the gut it was first identified in the human appendix in 1974[2]. Melatonin is synthesized in the pineal gland and secreted in a circadian pattern, with highest amounts released during nighttime[3]. The light/dark information regulating the secretion of melatonin by the pineal gland is received in the supra-chiasmatic nuclei via retinal photosensitive ganglionic cells. Melatonin released into the bloodstream acts as an endocrine hormone and controls biological functions with circadian rhythms, e.g., the sleep-wake cycle. Melatonin is also involved in the regulation of food intake and digestion[4].
Following the detection of the melatonin-synthesizing enzymes N-acetytransferase and hydroxyindole-O-methyltransferase in the gut[5], the possibility of additional extra-pineal melatonin synthesis was considered[6]. Melatonin produced in the gut is believed to act as a paracrine hormone which can be secreted in both a continuous or a cyclic fashion. Melatonin is also synthesized by a variety of other extra-pineal cells, such as bone marrow cells, lymphocytes, mast cells and epithelial cells, and it is unclear to what extent melatonin from these sources contributes to gut melatonin levels. Release of melatonin from all these extra-pineal sources seems to be independent of the photoperiod[7-9].
Melatonin has been studied in different areas of medicine in numerous clinical trials. In the lower gut, the roles of melatonin are complex and largely uncharacterized. This review will focus on the gastrointestinal (GI) localization of melatonin, the role of melatonin in the lower gut and the mechanisms involved. Animal and bench-side research, as well as translational human research, will be discussed with a special emphasis on summarizing all available human data related to the lower gut.
MELATONIN PRESENCE IN THE LOWER GUT
Bubenik et al[10] were the first to report the presence of melatonin in the mucosa of the gut. This observation was later confirmed by studies using immunohistochemistry and radioimmunoassay techniques[11]. In the mammalian gut, melatonin exhibits striking differences in regional distribution, with the highest levels in the rectum and the colon and the lowest levels in the jejunum and the ileum. These regional differences in tissue distribution were confirmed in other species including rabbit, mouse and human[12]. Moreover, specific antibodies against melatonin in rat identified melatonin-like immunoreactivity in all parts of the gut, and after administering exogenous melatonin the most pronounced accumulation of melatonin was seen in the colon and the rectum[13]. Furthermore, melatonin was detected in luminal fluids of the gut. This melatonin may originate from food, mucosal sources, or organisms populating the gut. Finally, luminal melatonin may also be of biliary origin, but at the present time its sources have not been elucidated.
Melatonin is synthesized in the enterochromaffin (EC) cells throughout the gut[14,15], and the EC cells have been reported to be the major source of L-tryptophan-induced increase of circulating melatonin. Interestingly, the distribution of melatonin is comparable to the density of EC cells in the gut. Oral administration of L-tryptophan caused a rapid and dose-dependent elevation of circulating melatonin in rats or chickens[16]. L-tryptophan-induced melatonin synthesis was greater following oral than following intraperitoneal administration. This indicates that L-tryptophan is a crucial precursor in gut melatonin synthesis.
Some melatonin detected in the gut is of pineal origin through accumulation from circulating sources, and the digestive tract, especially in the lower gut, might act as a store for pineal-derived melatonin particularly at nighttime[17]. Melatonin levels in the gut are independent of pineal production, since in rats pinealectomy had no influence on gut melatonin concentrations[18]. Interestingly, at any time of the day or night, the gut contains at least 400 times more melatonin than the pineal gland, once again emphasizing the functional importance of melatonin in the gut. No photoperiodic cyclical secretion of melatonin was observed in the gut, which is in contrast to the typical secretion pattern for melatonin from the pineal gland. In diabetic rats, lower melatonin levels were observed in the pancreas, the kidneys and the duodenum, but no change of melatonin level was detected in the colon, when compared to non-diabetic control rats[19]. The relevance of these observations has yet to be determined.
Melatonin concentrations in the gut vary depending on age. In the postnatal rat, GI melatonin levels peaked at birth and then declined to stable levels at the age of 21 d[13]. This decline in melatonin concentrations was more pronounced in the jejunum, ileum and colon compared to the stomach[20]. However, later in life the levels of melatonin increase; it has been shown that melatonin concentration in the mucosa of the ileum and distal colon is 126% higher in older mice (22-24 mo) compared to younger mice (2-5 mo)[21]. Remarkably, the same study provided evidence that most of the daytime levels of melatonin in the blood are of GI origin. It was also shown in pigs that the serum melatonin levels correlate well with the levels of melatonin in the lower gut[22]. Food restriction increases melatonin concentrations in the gut and in the brain in mice[23]. These distinct changes in melatonin levels suggest that there may be a physiological role for melatonin in the regulation of digestion and in the control of food intake. On the contrary, the melatonin levels in the lower gut may be influenced by luminal contents and may thus depend on the movement of digesta, but this notion remains speculative at the present stage.
MELATONIN RECEPTORS ARE LOCALIZED IN THE ILEUM AND THE COLON
Melatonin exerts some of its physiological effects through activation of specific membrane receptors. According to their pharmacological properties, these receptors have been classified as Mel1A, Mel1B and Mel1C[24,25]. Two of these, Mel1A and Mel1B, were recently renamed melatonin-1 receptor (MT1) and MT2 receptors. Both MT1 and MT2 receptors are members of the G-protein coupled receptor family and share a common seven transmembrane structure. MT1 and MT2 show high homology at the amino acid level, with a 55% overall homology and a 70% homology within the transmembrane domains. They also share some specific short amino acid sequences, suggesting that they represent a specific subfamily[26,27]. However, MT1 and MT2 receptors activate very distinct intracellular signaling pathways[28,29]. It has been shown that the MT1 melatonin receptor is coupled to G proteins that mediate adenylate cyclase inhibition and phospholipase C beta activation. The MT2 receptor couples to a number of signal transduction pathways, including phosphoinositol production, inhibition of adenylate cyclase and the inhibition of soluble guanylate cyclase pathway[30-32]. Luzindole acts as an antagonist at both receptors and is used in numerous studies[33-35]. 4-P-PDOT is a selective antagonist at MT2[36]. For the MT1 receptor no highly selective antagonist has been reported yet.
The third melatonin binding site MT3 (formerly Mel1C) is an enzyme named quinone reductase 2 (QR2). MT3 can be blocked by prazosin. Activation of MT3/QR2 by melatonin may explain the protective effect of melatonin against oxidative stress in different animal models, since MT3/QR2 has potent antioxidant properties.
The melatonin receptors display regional tissue and cell specific variations, reflecting the overall complexity of melatonin signaling[37]. Functional assays, as well as receptor binding studies, have demonstrated the presence of high affinity binding sites for melatonin on cell membranes, for example in the hypothalamus, medulla oblongata, hippocampus, cerebellum, parietal cortex and striatum of rats. Interestingly, the density of these binding sites varies depending on the time of the day and physiological conditions, including age[38,39].
Furthermore, there exists a group of nuclear melatonin receptors. These nuclear receptors for melatonin belong to the retinoid Z receptor (RZR) or retinoid orphan receptor (ROR) subfamilies, which include three subtypes (α, β, γ), encoded by three different genes[40,41]. An interaction between membrane and nuclear melatonin receptors was suggested by the observation that the expression of ROR/RZR mRNA is decreased in blood mononuclear cells with reduced MT1 receptor expression. Finally, melatonin can directly interact with intracellular proteins such as calmodulin, calreticulin or tubulin, extending the list of potential sites of binding and action for melatonin[42-44].
All three MT receptors can be found in the gut and the data on localization are summarized in Table 1. The sub-cellular distribution of melatonin binding is highest in the nuclear fraction, followed by the microsomal and the mitochondrial fractions, and is lowest in the cytosolic fraction.
Table 1
Table 1
Localization of melatonin membrane receptors in the ileum and the colon of rodents
Melatonin MT1 receptor mRNA has been detected in rat small and large intestine. The highest MT1 mRNA expression was found in the rat duodenum, with lower expression in the jejunum and ileum. No circadian changes were found in MT1 mRNA expression in gut tissues. In the duck gut, there was found to be a significant variation in the densities of 2-iodo (125I)-melatonin binding sites in different regions of the gut, with the following descending order of density: ileum, jejunum > duodenum, colon > cecum > esophagus[45]. Short-term fasting increased the expression of MT1 in the sub-epithelial layer of the rat small and large intestine, but no changes in MT1 expression were detected in other gut layers. During long-term fasting this increase in MT1 expression persisted only in distal colon, while in the remainder of the colon and in the small intestine MT1 expression returned to normal levels[46-48].
A study using tissues from rat pancreas, stomach, duodenum and colon found the highest levels of MT2 in the colon by using western blot analysis[49]. In the same study, the most intense MT2 immunoreactivity was observed in the muscularis mucosae and in the circular and longitudinal muscle layers of rat gut. Detection of MT2 receptors in the gut muscle layers suggests an involvement of MT2 in the regulation of intestinal motility. Comparable to MT1, the expression of MT2 receptors does not vary with food intake.
Pharmacological studies suggested the presence of the melatonin MT3 receptor in guinea pig colon[50] and later MT3 was found in monkey (Macaca fascicularicus) gut[51]. However, presently it is unclear in which gut layer MT3 is expressed.
In addition, in blood vessels of both rodent and human colon, a high density of melatonin-binding sites was reported. In vitro preparations of arterial smooth muscle of the porcine colon relax in response to melatonin and melatonin receptor agonists, although these effects were seen at rather high concentrations of melatonin[52]. Based on in vitro experiments on rat arteries, it has been suggested that a vasoconstrictive effect of melatonin is mediated via MT1 and a vasodilatatory effect is mediated via MT2 receptors[53]. The effects of melatonin in the gut may be dose-dependent and reflect actual MT1/MT2 ratio in muscle layers of gut segments.
Whereas data are available for the localization and expression of MT receptors in the gut, the presence of nuclear melatonin binding sites remains unresolved. One study has suggested that melatonin nuclear receptors are present in murine colon cancer cells, but the relevance of this observation and localization remains unclear[54].
ACTIONS OF MELATONIN IN THE ILEUM AND THE COLON
In contrast to the central nervous system, the function of melatonin in the gut is less clear. In the gut it seems that melatonin plays significant roles in regulating intestinal motility, the immune system, GI secretion, and the release of peptides involved in energy balance such as peptide YY[55]. Melatonin was also shown to protect the colon in different pathophysiological conditions; frequently these protective effects involve activation of antioxidative mechanisms or the regulation of blood vessel tone and thus modification of perfusion[56,57]. Another effect of melatonin is the alteration of gut flora and potential anti-microbiotic actions; melatonin was shown to influence E. coli O157:H7 growth in vitro and in vivo in infected wethers[58].
Motility
Melatonin is known to be involved in the regulation of GI motility. Melatonin is produced in EC cells of the GI tract and has high lipophilicity, and therefore may diffuse into deeper layers through mucosa and submucosa, to finally act in the muscularis mucosae or the myenteric plexus. In these actions, muscular and neuronal sites are involved. Contractile and relaxant effects of melatonin in the GI tract have been reported in numerous species[59-61]. The involved sites of action and the mechanism of melatonin action in the GI tract are not poorly characterized. Involvement of melatonin receptors and/or ion channels located on GI smooth muscle cells and/or neurons have been suggested and details are discussed below.
Melatonin alters GI motility by activating melatonin receptors. The most likely sites of melatonin action in the GI smooth muscle cells are the membrane-bound melatonin receptors and there is strong evidence that MT2 receptors are involved. In vivo animal studies showed that melatonin exerted both excitatory and inhibitory effects on the gut depending on the dose of melatonin. Small doses of melatonin accelerated the intestinal transit in rats, while high doses reversed this effect. These effects were blocked by luzindole, suggesting the involvement of intestinal melatonin receptors[62].
Early in vitro research showed that melatonin reduces the force of spontaneous contractions of ileum and colon segments of rat intestine, while the frequency of intestinal contractions remained unchanged[61]. In the GI tract, the cyclic generation of electrical currents is one fundamental mechanism of coordinated smooth muscle contraction. Slow waves and spiking activity are organized in myoelectric migrating complexes (MMC). Depending on the report, endogenous and exogenous melatonin inhibits pre- and postprandial irregular spiking activity of intestinal motility. Furthermore, pinealectomy suppressed the regular phase of MMCs, and administration of exogenous melatonin could restore a regular phase MMC activity in rat ileum[63]. These changes may depend on the action of melatonin on the GI neurons. In one study focusing on gastric emptying, melatonin partly inhibited gastric motility by activating sympathetic neurons. In the stomach, melatonin also reduces nitrergic myenteric innervation[64]. In electrophysiological experiments it was shown that the nitrergic component of the smooth muscle inhibitory junction potential was reduced by melatonin and this may be a consequence of direct inhibition of nitric oxide synthase (NOS) activity by melatonin at enteric synapses. Other studies suggest that the effect of melatonin may be related to the blockade of nicotinic channels by melatonin, or due to an interaction between melatonin and Ca2+-activated K+ channels[65]. Furthermore, it was demonstrated that the inhibitory effect of melatonin is apamin-sensitive and thus involves Ca2+-activated K+ channels[66]. One study also showed that the melatoninergic attenuation of acetylcholine-induced contractions of intestinal strips from goldfish is dependent on extracellular calcium[67].
Moreover, a beneficial effect of melatonin in reversing lipopolysaccaride-induced motility disturbances, which involves a reduction in lipid peroxidation and an increase of mitogen-activated protein kinase activation, nuclear factor kappaB (NF-κB) activation, inducible NOS (iNOS; NOS-2) expression and finally nitrite production[68], was reported. Additionally, melatonin was shown to modulate the cholecystokinin action on ileal motility and to reduce the duration of cholecystokinin stimulatory effects on GI smooth muscle in rats[69].
Other possible sites of melatonin action are 5-HT receptors. One study suggested that high doses of melatonin in the GI tract interact with cholecystokinin-2 and 5-HT3 receptors on the vagal afferent fibers, and thus induce vago-vagal inhibitory reflexes[70]. In some reports, the relaxant effect of melatonin through 5-HT receptor antagonism was proven[71], but other pathways may also be involved. Recently, it was demonstrated that melatonin can inhibit the activity of the serotonin transporter, which controls the reuptake of 5-HT in intestinal epithelial cells and inhibits NK₂ receptor-triggered 5-HT release from guinea pig colonic mucosa by acting at a MT₃ melatonin receptor located directly on the mucosal layer[72]. These actions may at the same time affect gut secretion.
Secretion
Melatonin is involved in the regulation of intestinal ion transport. Exogenous melatonin reduced diarrhea in rats with colitis, but the involved mechanisms have not been fully elucidated[73]. In the colon, melatonin is thought to play a role in regulating Cl secretion[74]. Melatonin can affect the expression of COX-2 and iNOS and melatonin modulates secretion elicited by prostaglandin E2 and sodium nitroprusside in rat distal colon. Some of these secretory effects seem to be localized in the colonic epithelium and involve cAMP pathways, while others involve the enteric neuronal system[75]. According to these studies, melatonin is a physiological modulator of ion transportation in the lower gut and many mechanisms are involved.
Immune system
Melatonin has numerous effects on the immune system. It increases natural killer cell activity and Th2 cell-mediated immune responses[76,77]. Melatonin was reported to regulate gene expression of several cytokines including IL-2, IL-2R and IFN-γ released by human CD4 T cells[78,79]. The effects on other functions of the immune system, such as lymphoproliferation and cytokine production by human lymphocytes, have also been studied. Melatonin protects human and murine CD4+ T cells from apoptosis by inhibiting CD95 ligand mRNA and protein up-regulation in response to TCR/CD3 stimulation[80]. Additionally, the melatonin/IL-2 relationship may be particularly relevant for immune tolerance. Melatonin can affect T-cell tolerance via IL-2[81]. At the same time, melatonin acts as an immunomodulator and these effects are mediated by melatonin receptors located on immunocompetent cells[82]. Melatonin synthesized in human lymphocytes is involved in the physiological regulation of IL-2/IL-2R expression through mechanisms comprising both membrane and nuclear melatonin receptors[83].
The majority of melatonin effects described for lymphocytes seem to be mediated through MT1 receptors[84]. However, some evidence shows that melatonin-induced enhancement of immune function is also mediated via MT2 receptors[85]. Antagonists at the MT2 receptor or the nuclear RZR/ROR were found to reduce human lymphocyte IL-2 production, proving the involvement of these binding sites in IL-2 production[86].
Experimental inflammation
By preserving the mucosal cell integrity and inhibiting the accumulation of neutrophils, melatonin exerts protective effects against inflammation in the gut[87]. Melatonin was shown to reduce the severity of intestinal inflammatory pathologies such as colitis in animal models[88]. Pentney et al[89] reported that daily melatonin administration reduced the severity of dextran sodium sulphate (DSS)-induced colitis in mice. In these experiments, serum melatonin levels were more than 10 times higher in mice that received DSS, as compared to controls. It is presently unclear what causes the significant improvement of inflammation in melatonin-treated mice, as no receptor antagonists were employed in this study and no downstream mechanisms were investigated.
Melatonin has been reported to reduce the severity of experimental colitis in mice and rats and though in vitro and in vivo studies suggest numerous pathways involved, the exact mechanism of action remains unclear[90]. In experimental colitis in rats, melatonin reduced colon injury by influencing numerous events including the enzyme activities of matrix metalloproteinase-9 (MMP-9), MMP-2 and caspase-3, by suppressing the activities of cyclooxygenase-2 (COX-2) and iNOS, inhibiting the expression of NF-κB and acting as a radical scavenger[91-95]. Moreover, the regulation of macrophage activity[96] and the reduction of bacterial translocation in trinitrobenzene sulfonic acid (TNBS)-induced colitis have been reported[97]. Melatonin treatment also causes a substantial reduction of FasL gene activation, which is known to induce a pro-inflammatory response characterized by a release of IL-1b, macrophage inflammatory protein-1a (MIP-1a), MIP-1b and MIP-2. Blocking the action of these cytokines has been shown to delay the onset of experimental colitis, to suppress inflammation and to ameliorate colonic damage[98]. But melatonin does not exert unanimously protective effects. Marquez et al[99] reported that acutely administered melatonin is protective against TNBS-induced colitis in rats, whereas chronic melatonin treatment exaggerates colitis. Future studies are needed to clarify the full extent of melatonin protection against colitis and to characterize the involved mechanisms.
ROLE OF MELATONIN IN DISEASES INVOLVING THE ILEUM AND THE COLON
Irritable bowel syndrome
Irritable bowel syndrome (IBS) is a functional GI disorder characterized by abdominal pain and is diagnosed following the Rome III criteria. Multiple factors are involved in the pathophysiology of IBS; amongst others IBS has been associated with abnormal GI motor functions, visceral hypersensitivity, as well as psychosocial factors[100,101].
Some studies suggest a possible role of melatonin in the pathophysiology of IBS. For example, disturbances in melatonin metabolism and secretion may be involved in different GI diseases including IBS[102]. In a clinical trial involving patients with IBS, the beneficial effects of melatonin were obvious in the relief of symptoms such as abdominal pain, abdominal distension and abnormal sensation of defecation[103]. Melatonin may exert its beneficial effects in IBS through effects on the central nervous system, via an enhancement of the cellular and humoral immune systems, or by antagonizing corticoid- and serotonin-mediated effects[104,105]. However, melatonin does not influence sleep pattern or psychological well-being in patients with IBS. Recently, it has been shown that the antinociceptive effects of melatonin are not mediated through melatonin receptors, but through a supra-spinal process linked to the central opioidergic system, as pre-treatment with naltrexone or luzindole blocked the antinociceptive effect of melatonin in TNBS-treated rats[106].
According to recent clinical trials, melatonin may be a future therapeutic option for IBS management (Table 2). In one placebo-controlled, randomized clinical trial in 40 patients with IBS, daily administration of melatonin 3 mg orally at bedtime for two weeks significantly alleviated abdominal pain[107]. Patients treated with melatonin for two weeks significantly increased rectal thresholds towards balloon pressure and volume, ameliorating rectal sensitivity to pain and urgency. In another clinical trial, 17 female IBS patients were randomized to receive either melatonin 3 mg or placebo at bedtime for 8 wk, followed by a 4-wk washout period[108]. Improvements in mean IBS scores were significantly greater during treatment with melatonin compared to placebo. Additionally, sleep, anxiety and depression scores improved. Saha et al[109] randomly assigned 18 IBS patients to receive either melatonin 3 mg or placebo at bedtime for 8 wk and they found that melatonin significantly improved overall IBS scores and quality of life scores. All these trials suggest that melatonin has beneficial effects in patients with IBS, but larger clinical trials in patients with IBS are needed. Another clinical trial was interested in colonic transit time (CTT) in IBS patients. These patients were randomized and received either melatonin 3 mg or placebo daily for 8 wk[110]. Neither in healthy controls, nor in IBS patients, were stool texture or CTT changed, but the tests used may not be sensitive enough to detect motility or secretory changes and thus these data need to be interpreted cautiously.
Table 2
Table 2
Clinical trials using melatonin in patients with irritable bowel syndrome
In some of these clinical trials it has been shown that the beneficial effects of melatonin in IBS may be related to its action on gut sensory pathways. In this context it would be interesting to know whether melatonin alters visceral hypersensitivity or whether it acts as a general analgesic and would reduce rectal sensations in healthy volunteers as well. It is presently not clear whether this melatonin effect on rectal sensation is short-lasting or holds over longer periods of time. Although only a few clinical studies have shown its efficacy, melatonin appears to have a significant role in reduction of abdominal distension and rectal pain in treatment of IBS.
Inflammatory bowel disease
Despite the numerous animal studies showing protective effects of melatonin in colitis models, there are only limited clinical data available on the therapeutic role of melatonin in inflammatory bowel disease (IBD). To our knowledge, there are three published case reports of the self-administration of melatonin in IBD (Table 3). However, no clinical trials have been performed in IBD patients.
Table 3
Table 3
Case reports of melatonin self administration in patients with ulcerative colitis and Crohn’s disease
In one case report, after the self-administered use of melatonin as a self directed treatment for jet lag on international flights, the patient observed that his ulcerative colitis (UC) symptoms were virtually absent[111,112]. Once his flare-ups were more troublesome requiring continuous topical mesalamine therapy, he self-administered melatonin 3 mg/d, and according to the report he was symptom-free for a period of 3 mo. His symptoms recurred within 1 wk of running out of melatonin tablets. In contrast, other cases showed melatonin exacerbated symptoms associated with UC or Crohn’s disease[113,114]. One patient decided to take melatonin capsules (3 mg) at bedtime. Two months later, the patient started to experience the symptoms of active UC, including bloody mucous diarrhea. He continued taking melatonin and received corticosteroids orally and rectally. Since the symptoms did not calm down, the patient was hospitalized and stopped consuming melatonin; 48 h later there was a complete remission of the UC symptoms. Another patient decided to take melatonin capsules (3 mg) at bedtime. Four days later, the patient started to experience the symptoms of active Crohn’s disease, such as diarrhea and abdominal cramps. She then stopped taking melatonin, and 24 h later there was a complete remission of symptoms. Clinical trials should be performed to evaluate a possible beneficial or detrimental effect of melatonin in IBD; presently available literature is inconclusive, though basic studies strongly suggest beneficial effects.
Colon cancer
Following the identification of melatonin binding sites in human colon tissue from patients with carcinoma of the rectum and the colon, a possible role of melatonin in colorectal cancer was addressed in several studies. 125I-melatonin binding sites were identified in the mucosa and the submucosa of the human colon and radioimmunoassays revealed melatonin concentrations of 467 ± 99 pg/g tissue in non-cancer control patients, while daytime melatonin concentrations in the colon of patients with colorectal carcinoma were 3147 ± 87.8 pg/g tissue[115]. The relevance of the diurnal variation of melatonin levels to colon cancer has yet to be determined. Colorectal carcinoma patients showed significant decrements in the peak amplitude of melatonin secretion, as well as a reduction in overall melatonin output[116]. Some studies suggest that melatonin may be involved in cancer risk or protection from cancer development[117]. For example, following pinealectomy, increased colonic crypt cell proliferation was reported in rats, suggesting melatonin pathways being involved in carcinogenesis in the colon[118]. Another study in rats showed that small bowel crypt cell hyperplasia occurred several weeks after pinealectomy, but again the exact mechanisms were not identified. Recently, melatonin showed a great potential to control the preneoplastic patterns induced by constant light in the colon[119].
The suggested colon cancer controlling mechanism of melatonin involves inhibition of tumour angiogenesis, modulation of the mitotic and apoptotic indices, and maintenance of the intracellular level of glutathione[120,121]. Although no effects of melatonin on in vitro cell growth were found, a statistically significant and progressive suppression of de novo DNA synthesis was found following melatonin application[122]. Other melatonin effects related to the control of tumour growth are the modulation of estrogen receptors, direct effects on the cell cycle, influence on several growth factors, increasing of gap junctions and enhancing the level of anti-oxidants[123,124]. The anti-oxidative and anti-inflammatory actions of melatonin, changing the oxidative status and reducing the production of nitric oxide by cultured colon cancer cells, may also be directly involved in the oncostatic properties of melatonin[125]. Some studies suggest that for colon adenocarcinoma, membrane-bound and nuclear melatonin receptors are involved in these oncostatic actions[126,127]. Melatonin binds to receptors on T helper cells and monocytes, stimulating the production of IFNγ and interleukins 1, 2, 6 and 12, which in turn up-regulates immune responses resulting in a restoration of immunodeficiency states[128]. Melatonin in this context also modulates the expression of NF-κB, TNF-α, IL-1β and STAT3[129]. The activation of lymphocytes and monocytes/macrophages by melatonin is one of the mechanisms by which melatonin as an immunosurveillant prevents tumor development[130,131]. For example, patients with advanced GI carcinoma treated with a combination of IL-2 and melatonin exhibited a significantly higher number of lymphocytes, T lymphocytes, NK cells and CD4+ cells than those receiving IL-2 alone[132].
In clinical trials, melatonin was shown to have cytoprotective effects that may be involved in increasing the efficacy of cancer chemotherapy and improving survival. Melatonin co-treatment was also shown to reduce the adverse toxicities of chemotherapy and radiotherapy in several studies, including in patients with colorectal carcinoma[133,134]. For example, the efficacy of weekly low-dose CPT-11 in pretreated metastatic colorectal cancer patients may be enhanced by a concomitant daily admi-nistration of melatonin (20 mg/d, orally)[135]. Other clinical studies showed that melatonin co-treatment with IL-2, Aloe vera or fish oil partly enhanced the effect of chemotherapy and reduced the toxicity in colorectal carcinoma[136-139]. However, melatonin did not have any protective effect on irradiation-induced lymphocytopenia in patients with colorectal carcinoma (Table 4)[140].
Table 4
Table 4
Clinical trials using melatonin in patients with colorectal cancer
Clinical trials using melatonin in the context of colorectal cancer are small and unfortunately not of high quality. Presently, these studies have to be carefully interpreted and the studies seem, if anything, to be hypothesis-generating. Controlled clinical trials are needed to establish the potential role of melatonin in cancer treatment.
CONCLUSION
Melatonin found in the lower gut comes largely from intestinal sources, such as the EC cells and, to only a minor extent, from extra-intestinal sources such as the pineal gland. Melatonin levels in the ileum and the colon are dependent on food intake and digestion, but in contrast to systemic melatonin levels, the GI melatonin level is independent of light or the circadian rhythm.
Melatonin regulates the motility of the lower gut by acting on membrane melatonin receptors and all known MT1-3 were found to be localized in the GI tract, though their exact involvement in the regulation is not fully characterized. Additionally, actions of melatonin on 5-HT receptors have been reported, adding to the complexity of melatonin involvement in the regulation of GI function.
Melatonin was recently suggested to be a promising future drug for IBS treatment. Presently available basic and clinical data indicate that it is particularly effective in alleviating hypersensitivity and pain in patients with IBS, but larger clinical trials, ideally double-blinded and placebo-controlled, are needed.
Melatonin is furthermore involved in immunomodulatory functions throughout the GI tract. The protective actions of melatonin in mouse models of intestinal inflammation or in models of GI cancer are promising and warrant further research. The translation of these observations to humans is less well characterized.
Footnotes
Peer reviewers: John R Grider, PhD, Professor, Department of Physiology & Biophysics, Virginia Commonwealth University, PO Box 980551, Richmond, VA 23298, United States; Angelo A Izzo, Professor, Department of Experimental Pharmacology, University of Naples Federico II, Via D Montesano 49, 80131 Naples, Italy
S- Editor Tian L L- Editor Logan S E- Editor Li JY
References
1.
Messner M, Huether G, Lorf T, Ramadori G. ,Schworer H. Presence of melatonin in the human hepatobiliary-gastrointestinal tract. Life Sci. 2001;69:543-551. [DOI]
2.
Bubenik GA. Thirty four years since the discovery of gastrointestinal melatonin. J Physiol Pharmacol. 2008;59 Suppl 2:33-51.[PubMed]
3.
Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336:186-195.[PubMed] [DOI]
4.
Bubenik GA, Hacker RR, Brown GM, Bartos L. Melatonin concentrations in the luminal fluid, mucosa, and muscularis of the bovine and porcine gastrointestinal tract. J Pineal Res. 1999;26:56-63.[PubMed] [DOI]
5.
Hong GX, Pang SF. N-acetyltransferase activity in the quail (Coturnix coturnix jap) duodenum. Comp Biochem Physiol B Biochem Mol Biol. 1995;112:251-255.[PubMed] [DOI]
6.
Stefulj J, Hörtner M, Ghosh M, Schauenstein K, Rinner I, Wölfler A, Semmler J, Liebmann PM. Gene expression of the key enzymes of melatonin synthesis in extrapineal tissues of the rat. J Pineal Res. 2001;30:243-247.[PubMed] [DOI]
7.
Maldonado MD, Mora-Santos M, Naji L, Carrascosa-Salmoral MP, Naranjo MC, Calvo JR. Evidence of melatonin synthesis and release by mast cells. Possible modulatory role on inflammation. Pharmacol Res. 2010;62:282-287.[PubMed] [DOI]
8.
Maestroni GJ. The immunotherapeutic potential of melatonin. Expert Opin Investig Drugs. 2001;10:467-476.[PubMed] [DOI]
9.
Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res. 2000;28:193-202.[PubMed] [DOI]
10.
Bubenik GA, Brown GM, Bubenik AB, Grota LJ. Immunohistological localization of testosterone in the growing antler of the white-tailed deer (Odocoileus virginianus). Calcif Tissue Res. 1974;14:121-130.[PubMed] [DOI]
11.
Menendez-Pelaez A, Poeggeler B, Reiter RJ, Barlow-Walden L, Pablos MI, Tan DX. Nuclear localization of melatonin in different mammalian tissues: immunocytochemical and radioimmunoassay evidence. J Cell Biochem. 1993;53:373-382.[PubMed] [DOI]
12.
Poon AM, Chow PH, Mak AS, Pang SF. Autoradiographic localization of 2[125I]iodomelatonin binding sites in the gastrointestinal tract of mammals including humans and birds. J Pineal Res. 1997;23:5-14.[PubMed] [DOI]
13.
Bubenik GA. Localization of melatonin in the digestive tract of the rat. Effect of maturation, diurnal variation, melatonin treatment and pinealectomy. Horm Res. 1980;12:313-323.[PubMed] [DOI]
14.
Huether G. The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Experientia. 1993;49:665-670.[PubMed] [DOI]
15.
Kvetnoy IM, Ingel IE, Kvetnaia TV, Malinovskaya NK, Rapoport SI, Raikhlin NT, Trofimov AV, Yuzhakov VV. Gastrointestinal melatonin: cellular identification and biological role. Neuro Endocrinol Lett. 2002;23:121-132.[PubMed]
16.
Huether G, Poeggeler B, Reimer A, George A. Effect of tryptophan administration on circulating melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract. Life Sci. 1992;51:945-953.[PubMed] [DOI]
17.
Huether G, Messner M, Rodenbeck A, Hardeland R. Effect of continuous melatonin infusions on steady-state plasma melatonin levels in rats under near physiological conditions. J Pineal Res. 1998;24:146-151.[PubMed] [DOI]
18.
Bubenik GA, Brown GM. Pinealectomy reduces melatonin levels in the serum but not in the gastrointestinal tract of rats. Biol Signals. 1997;6:40-44. [DOI]
19.
Stebelová K, Herichová I, Zeman M. Diabetes induces changes in melatonin concentrations in peripheral tissues of rat. Neuro Endocrinol Lett. 2007;28:159-165.[PubMed]
20.
Bubenik GA, Pang SF. The role of serotonin and melatonin in gastrointestinal physiology: ontogeny, regulation of food intake, and mutual serotonin-melatonin feedback. J Pineal Res. 1994;16:91-99.[PubMed] [DOI]
21.
Bertrand PP, Bertrand RL, Camello PJ, Pozo MJ. Simultaneous measurement of serotonin and melatonin from the intestine of old mice: the effects of daily melatonin supplementation. J Pineal Res. 2010;49:23-34.[PubMed] [DOI]
22.
Bubenik GA, Pang SF, Hacker RR, Smith PS. Melatonin concentrations in serum and tissues of porcine gastrointestinal tract and their relationship to the intake and passage of food. J Pineal Res. 1996;21:251-256.[PubMed] [DOI]
23.
Bubenik GA, Ball RO, Pang SF. The effect of food deprivation on brain and gastrointestinal tissue levels of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin. J Pineal Res. 1992;12:7-16.[PubMed] [DOI]
24.
Barrett P, Conway S, Morgan PJ. Digging deep--structure-function relationships in the melatonin receptor family. J Pineal Res. 2003;35:221-230.[PubMed] [DOI]
25.
Dubocovich ML. Melatonin receptors: are there multiple subtypes?. Trends Pharmacol Sci. 1995;16:50-56.[PubMed] [DOI]
26.
Masana MI, Dubocovich ML. Melatonin receptor signaling: finding the path through the dark. Sci STKE. 2001;2001:pe39.[PubMed] [DOI]
27.
Jockers R, Maurice P, Boutin JA, Delagrange P. Melatonin receptors, heterodimerization, signal transduction and binding sites: what's new?. Br J Pharmacol. 2008;154:1182-1195.[PubMed] [DOI]
28.
von Gall C, Stehle JH, Weaver DR. Mammalian melatonin receptors: molecular biology and signal transduction. Cell Tissue Res. 2002;309:151-162.[PubMed] [DOI]
29.
Witt-Enderby PA, Bennett J, Jarzynka MJ, Firestine S, Melan MA. Melatonin receptors and their regulation: biochemical and structural mechanisms. Life Sci. 2003;72:2183-2198.[PubMed] [DOI]
30.
Bondi CD, McKeon RM, Bennett JM, Ignatius PF, Brydon L, Jockers R, Melan MA, Witt-Enderby PA. MT1 melatonin receptor internalization underlies melatonin-induced morphologic changes in Chinese hamster ovary cells and these processes are dependent on Gi proteins, MEK 1/2 and microtubule modulation. J Pineal Res. 2008;44:288-298.[PubMed] [DOI]
31.
Chan ASL, Lai FPL, Lo RKH, Voyno-Yasenetskaya TA, Stanbridge EJ, Wong YH. Melatonin mt1 and MT2 receptors stimulate c-Jun N-terminal kinase via pertussis toxin-sensitive and -insensitive G proteins. Cell Signal. 2002;14:249-257. [DOI]
32.
Ho MK, Yung LY, Chan JS, Chan JH, Wong CS, Wong YH. Galpha(14) links a variety of G(i)- and G(s)-coupled receptors to the stimulation of phospholipase C. Br J Pharmacol. 2001;132:1431-1440.[PubMed] [DOI]
33.
Reppert SM, Weaver DR, Godson C. Melatonin receptors step into the light: cloning and classification of subtypes. Trends Pharmacol Sci. 1996;17:100-102.[PubMed] [DOI]
34.
Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci USA. 1995;92:8734-8738.[PubMed] [DOI]
35.
Shiu SY, Ng N, Pang SF. A molecular perspective of the genetic relationships of G-protein coupled melatonin receptor subtypes. J Pineal Res. 1996;20:198-204.[PubMed] [DOI]
36.
Lucarini S, Bedini A, Spadoni G, Piersanti G. An improved synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT): a selective MT(2) melatonin receptor antagonist. Org Biomol Chem. 2008;6:147-150.[PubMed] [DOI]
37.
Anisimov SV, Popovic N. Genetic aspects of melatonin biology. Rev Neurosci. 2004;15:209-230.[PubMed] [DOI]
38.
Zisapel N, Laudon M. Dopamine release induced by electrical field stimulation of rat hypothalamus in vitro: inhibition by melatonin. Biochem Biophys Res Commun. 1982;104:1610-1616.[PubMed] [DOI]
39.
Laudon M, Nir I, Zisapel N. Melatonin receptors in discrete brain areas of the male rat. Impact of aging on density and on circadian rhythmicity. Neuroendocrinology. 1988;48:577-583.[PubMed] [DOI]
40.
Carlberg C. Gene regulation by melatonin. Ann N Y Acad Sci. 2000;917:387-396.[PubMed]
41.
Hirose T, Smith RJ, Jetten AM. ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle. Biochem Biophys Res Commun. 1994;205:1976-1983.[PubMed] [DOI]
42.
Benítez-King G. Melatonin as a cytoskeletal modulator: implications for cell physiology and disease. J Pineal Res. 2006;40:1-9.[PubMed] [DOI]
43.
Macías M, Escames G, Leon J, Coto A, Sbihi Y, Osuna A, Acuña-Castroviejo D. Calreticulin-melatonin. An unexpected relationship. Eur J Biochem. 2003;270:832-840.[PubMed] [DOI]
44.
Meléndez J, Maldonado V, Ortega A. Effect of melatonin on beta-tubulin and MAP2 expression in NIE-115 cells. Neurochem Res. 1996;21:653-658.[PubMed] [DOI]
45.
Lee PP, Pang SF. Melatonin and its receptors in the gastrointestinal tract. Biol Signals. 1993;2:181-193.[PubMed] [DOI]
46.
Sallinen P, Saarela S, Ilves M, Vakkuri O, Leppäluoto J. The expression of MT1 and MT2 melatonin receptor mRNA in several rat tissues. Life Sci. 2005;76:1123-1134.[PubMed] [DOI]
47.
Soták M, Mrnka L, Pácha J. Heterogeneous expression of melatonin receptor MT1 mRNA in the rat intestine under control and fasting conditions. J Pineal Res. 2006;41:183-188.[PubMed] [DOI]
48.
Poirel VJ, Cailotto C, Streicher D, Pévet P, Masson-Pévet M, Gauer F. MT1 melatonin receptor mRNA tissular localization by PCR amplification. Neuro Endocrinol Lett. 2003;24:33-38.[PubMed]
49.
Stebelová K, Anttila K, Mänttäri S, Saarela S, Zeman M. Immunohistochemical definition of MT(2) receptors and melatonin in the gastrointestinal tissues of rat. Acta Histochem. 2010;112:26-33.[PubMed] [DOI]
50.
Santagostino-Barbone MG, Masoero E, Spelta V, Lucchelli A. 2-Phenylmelatonin: a partial agonist at enteric melatonin receptors. Pharmacol Toxicol. 2000;87:156-160.[PubMed] [DOI]
51.
Nosjean O, Nicolas JP, Klupsch F, Delagrange P, Canet E, Boutin JA. Comparative pharmacological studies of melatonin receptors: MT1, MT2 and MT3/QR2. Tissue distribution of MT3/QR2. Biochem Pharmacol. 2001;61:1369-1379.[PubMed] [DOI]
52.
Ting N, Thambyraja A, Sugden D, Scalbert E, Delagrange P, Wilson VG. Pharmacological studies on the inhibitory action of melatonin and putative melatonin analogues on porcine vascular smooth muscle. Naunyn Schmiedebergs Arch Pharmacol. 2000;361:327-333.[PubMed] [DOI]
53.
Doolen S, Krause DN, Dubocovich ML, Duckles SP. Melatonin mediates two distinct responses in vascular smooth muscle. Eur J Pharmacol. 1998;345:67-69.[PubMed] [DOI]
54.
Winczyk K, Pawlikowski M, Guerrero JM, Karasek M. Possible involvement of the nuclear RZR/ROR-alpha receptor in the antitumor action of melatonin on murine Colon 38 cancer. Tumour Biol. 2002;23:298-302.[PubMed] [DOI]
55.
Aydin M, Canpolat S, Kuloğlu T, Yasar A, Colakoglu N, Kelestimur H. Effects of pinealectomy and exogenous melatonin on ghrelin and peptide YY in gastrointestinal system and neuropeptide Y in hypothalamic arcuate nucleus: immunohistochemical studies in male rats. Regul Pept. 2008;146:197-203.[PubMed] [DOI]
56.
Reiter RJ. Melatonin: clinical relevance. Best Pract Res Clin Endocrinol Metab. 2003;17:273-285.[PubMed] [DOI]
57.
Konturek PC, Konturek SJ, Brzozowski T, Dembinski A, Zembala M, Mytar B, Hahn EG. Gastroprotective activity of melatonin and its precursor, L-tryptophan, against stress-induced and ischaemia-induced lesions is mediated by scavenge of oxygen radicals. Scand J Gastroenterol. 1997;32:433-438.[PubMed] [DOI]
58.
Schultz CL, Edrington TS, Callaway TR, Schroeder SB, Hallford DM, Genovese KJ, Anderson RC, Nisbet DJ. The influence of melatonin on growth of E. coli O157: H7 in pure culture and exogenous melatonin on faecal shedding of E. coli O157: H7 in experimentally infected wethers. Lett Appl Microbiol. 2006;43:105-110.[PubMed] [DOI]
59.
Lucchelli A, Santagostino-Barbone MG, Tonini M. Investigation into the contractile response of melatonin in the guinea-pig isolated proximal colon: the role of 5-HT4 and melatonin receptors. Br J Pharmacol. 1997;121:1775-1781.[PubMed] [DOI]
60.
Storr M, Schusdziarra V, Allescher HD. Inhibition of small conductance K+ -channels attenuated melatonin-induced relaxation of serotonin-contracted rat gastric fundus. Can J Physiol Pharmacol. 2000;78:799-806.[PubMed]
61.
Harlow HJ, Weekley BL. Effect of melatonin on the force of spontaneous contractions of in vitro rat small and large intestine. J Pineal Res. 1986;3:277-284.[PubMed] [DOI]
62.
Drago F, Macauda S, Salehi S. Small doses of melatonin increase intestinal motility in rats. Dig Dis Sci. 2002;47:1969-1974.[PubMed] [DOI]
63.
Merle A, Delagrange P, Renard P, Lesieur D, Cuber JC, Roche M, Pellissier S. Effect of melatonin on motility pattern of small intestine in rats and its inhibition by melatonin receptor antagonist S 22153. J Pineal Res. 2000;29:116-124.[PubMed] [DOI]
64.
Storr M, Koppitz P, Sibaev A, Saur D, Kurjak M, Franck H, Schusdziarra V, Allescher HD. Melatonin reduces non-adrenergic, non-cholinergic relaxant neurotransmission by inhibition of nitric oxide synthase activity in the gastrointestinal tract of rodents in vitro. J Pineal Res. 2002;33:101-108.[PubMed] [DOI]
65.
Barajas-López C, Peres AL, Espinosa-Luna R, Reyes-Vázquez C, Prieto-Gómez B. Melatonin modulates cholinergic transmission by blocking nicotinic channels in the guinea-pig submucous plexus. Eur J Pharmacol. 1996;312:319-325.[PubMed] [DOI]
66.
Reyes-Vázquez C, Naranjo-Rodríguez EB, García-Segoviano JA, Trujillo-Santana JT, Prieto-Gómez B. Apamin blocks the direct relaxant effect of melatonin on rat ileal smooth muscle. J Pineal Res. 1997;22:1-8.[PubMed] [DOI]
67.
Velarde E, Alonso-Gómez AL, Azpeleta C, Isorna E, Delgado MJ. Melatonin attenuates the acetylcholine-induced contraction in isolated intestine of a teleost fish. J Comp Physiol B. 2009;179:951-959.[PubMed] [DOI]
68.
De Filippis D, Iuvone T, Esposito G, Steardo L, Arnold GH, Paul AP, De Man Joris G, De Winter Benedicte Y. Melatonin reverses lipopolysaccharide-induced gastro-intestinal motility disturbances through the inhibition of oxidative stress. J Pineal Res. 2008;44:45-51.[PubMed]
69.
Bonouali-Pellissier S. Melatonin is involved in cholecystokinin-induced changes of ileal motility in rats. J Pineal Res. 1994;17:79-85.[PubMed] [DOI]
70.
Kasimay O, Cakir B, Devseren E, Yegen BC. Exogenous melatonin delays gastric emptying rate in rats: role of CCK2 and 5-HT3 receptors. J Physiol Pharmacol. 2005;56:543-553.[PubMed]
71.
Velarde E, Delgado MJ, Alonso-Gómez AL. Serotonin-induced contraction in isolated intestine from a teleost fish (Carassius auratus): characterization and interactions with melatonin. Neurogastroenterol Motil. 2010;22:e364-e373.[PubMed]
72.
Matheus N, Mendoza C, Iceta R, Mesonero JE, Alcalde AI. Melatonin inhibits serotonin transporter activity in intestinal epithelial cells. J Pineal Res. 2010;48:332-339.[PubMed] [DOI]
73.
Cuzzocrea S, Mazzon E, Serraino I, Lepore V, Terranova ML, Ciccolo A, Caputi AP. Melatonin reduces dinitrobenzene sulfonic acid-induced colitis. J Pineal Res. 2001;30:1-12.[PubMed] [DOI]
74.
Chan HC, Lui KM, Wong WS, Poon AM. Effect of melatonin on chloride secretion by human colonic T84 cells. Life Sci. 1998;62:2151-2158.[PubMed] [DOI]
75.
Mrnka L, Hock M, Rybová M, Pácha J. Melatonin inhibits prostaglandin E2- and sodium nitroprusside-induced ion secretion in rat distal colon. Eur J Pharmacol. 2008;581:164-170.[PubMed] [DOI]
76.
Raghavendra V, Singh V, Kulkarni SK, Agrewala JN. Melatonin enhances Th2 cell mediated immune responses: lack of sensitivity to reversal by naltrexone or benzodiazepine receptor antagonists. Mol Cell Biochem. 2001;221:57-62.[PubMed]
77.
Shaji AV, Kulkarni SK, Agrewala JN. Regulation of secretion of IL-4 and IgG1 isotype by melatonin-stimulated ovalbumin-specific T cells. Clin Exp Immunol. 1998;111:181-185.[PubMed] [DOI]
78.
Lardone PJ, Rubio A, Cerrillo I, Gómez-Corvera A, Carrillo-Vico A, Sanchez-Hidalgo M, Guerrero JM, Fernandez-Riejos P, Sanchez-Margalet V, Molinero P. Blocking of melatonin synthesis and MT(1) receptor impairs the activation of Jurkat T cells. Cell Mol Life Sci. 2010;67:3163-3172.[PubMed] [DOI]
79.
García-Mauriño S, Pozo D, Calvo JR, Guerrero JM. Correlation between nuclear melatonin receptor expression and enhanced cytokine production in human lymphocytic and monocytic cell lines. J Pineal Res. 2000;29:129-137.[PubMed] [DOI]
80.
Pedrosa AM, Weinlich R, Mognol GP, Robbs BK, Viola JP, Campa A, Amarante-Mendes GP. Melatonin protects CD4+ T cells from activation-induced cell death by blocking NFAT-mediated CD95 ligand upregulation. J Immunol. 2010;184:3487-3494.[PubMed] [DOI]
81.
Szczepanik M. Melatonin and its influence on immune system. J Physiol Pharmacol. 2007;58 Suppl 6:115-124.[PubMed]
82.
Maestroni GJ, Sulli A, Pizzorni C, Villaggio B, Cutolo M. Melatonin in rheumatoid arthritis: synovial macrophages show melatonin receptors. Ann N Y Acad Sci. 2002;966:271-275.[PubMed]
83.
Lardone PJ, Carrillo-Vico A, Molinero P, Rubio A, Guerrero JM. A novel interplay between membrane and nuclear melatonin receptors in human lymphocytes: significance in IL-2 production. Cell Mol Life Sci. 2009;66:516-525.[PubMed] [DOI]
84.
Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernández-Montesinos R, Guerrero JM, Pozo D. The modulatory role of melatonin on immune responsiveness. Curr Opin Investig Drugs. 2006;7:423-431.[PubMed]
85.
Drazen DL, Nelson RJ. Melatonin receptor subtype MT2 (Mel 1b) and not mt1 (Mel 1a) is associated with melatonin-induced enhancement of cell-mediated and humoral immunity. Neuroendocrinology. 2001;74:178-184.[PubMed] [DOI]
86.
Carrillo-Vico A, Lardone PJ, Fernández-Santos JM, Martín-Lacave I, Calvo JR, Karasek M, Guerrero JM. Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system. J Clin Endocrinol Metab. 2005;90:992-1000.[PubMed] [DOI]
87.
Ercan F, Cetinel S, Contuk G, Cikler E, Sener G. Role of melatonin in reducing water avoidance stress-induced degeneration of the gastrointestinal mucosa. J Pineal Res. 2004;37:113-121.[PubMed] [DOI]
88.
Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. Endocrine. 2005;27:189-200.[PubMed] [DOI]
89.
Pentney PT, Bubenik GA. Melatonin reduces the severity of dextran-induced colitis in mice. J Pineal Res. 1995;19:31-39.[PubMed] [DOI]
90.
Nosál'ová V, Zeman M, Cerná S, Navarová J, Zakálová M. Protective effect of melatonin in acetic acid induced colitis in rats. J Pineal Res. 2007;42:364-370.[PubMed] [DOI]
91.
Esposito E, Mazzon E, Riccardi L, Caminiti R, Meli R, Cuzzocrea S. Matrix metalloproteinase-9 and metalloproteinase-2 activity and expression is reduced by melatonin during experimental colitis. J Pineal Res. 2008;45:166-173.[PubMed] [DOI]
92.
Dong WG, Mei Q, Yu JP, Xu JM, Xiang L, Xu Y. Effects of melatonin on the expression of iNOS and COX-2 in rat models of colitis. World J Gastroenterol. 2003;9:1307-1311.[PubMed]
93.
Li JH, Yu JP, Yu HG, Xu XM, Yu LL, Liu J, Luo HS. Melatonin reduces inflammatory injury through inhibiting NF-kappaB activation in rats with colitis. Mediators Inflamm. 2005;2005:185-193.[PubMed] [DOI]
94.
Winiarska K, Fraczyk T, Malinska D, Drozak J, Bryla J. Melatonin attenuates diabetes-induced oxidative stress in rabbits. J Pineal Res. 2006;40:168-176.[PubMed] [DOI]
95.
Necefli A, Tulumoğlu B, Giriş M, Barbaros U, Gündüz M, Olgaç V, Güloğlu R, Toker G. The effect of melatonin on TNBS-induced colitis. Dig Dis Sci. 2006;51:1538-1545.[PubMed] [DOI]
96.
Mei Q, Yu JP, Xu JM, Wei W, Xiang L, Yue L. Melatonin reduces colon immunological injury in rats by regulating activity of macrophages. Acta Pharmacol Sin. 2002;23:882-886.[PubMed]
97.
Akcan A, Kucuk C, Sozuer E, Esel D, Akyildiz H, Akgun H, Muhtaroglu S, Aritas Y. Melatonin reduces bacterial translocation and apoptosis in trinitrobenzene sulphonic acid-induced colitis of rats. World J Gastroenterol. 2008;14:918-924.[PubMed] [DOI]
98.
Mazzon E, Esposito E, Crisafulli C, Riccardi L, Muià C, Di Bella P, Meli R, Cuzzocrea S. Melatonin modulates signal transduction pathways and apoptosis in experimental colitis. J Pineal Res. 2006;41:363-373.[PubMed] [DOI]
99.
Marquez E, Sánchez-Fidalgo S, Calvo JR, la de Lastra CA, Motilva V. Acutely administered melatonin is beneficial while chronic melatonin treatment aggravates the evolution of TNBS-induced colitis. J Pineal Res. 2006;40:48-55.[PubMed] [DOI]
100.
Guerrero JM, Reiter RJ. Melatonin-immune system relationships. Curr Top Med Chem. 2002;2:167-179.[PubMed] [DOI]
101.
Konturek SJ, Konturek PC, Brzozowska I, Pawlik M, Sliwowski Z, Cześnikiewicz-Guzik M, Kwiecień S, Brzozowski T, Bubenik GA, Pawlik WW. Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT). J Physiol Pharmacol. 2007;58:381-405.[PubMed]
102.
Radwan P, Skrzydlo-Radomanska B, Radwan-Kwiatek K, Burak-Czapiuk B, Strzemecka J. Is melatonin involved in the irritable bowel syndrome?. J Physiol Pharmacol. 2009;60 Suppl 3:67-70.[PubMed]
103.
Thor PJ, Krolczyk G, Gil K, Zurowski D, Nowak L. Melatonin and serotonin effects on gastrointestinal motility. J Physiol Pharmacol. 2007;58 Suppl 6:97-103.[PubMed]
104.
Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci. 2002;47:2336-2348.[PubMed]
105.
Maestroni GJ. The immunoneuroendocrine role of melatonin. J Pineal Res. 1993;14:1-10.[PubMed] [DOI]
106.
Mickle A, Sood M, Zhang Z, Shahmohammadi G, Sengupta JN, Miranda A. Antinociceptive effects of melatonin in a rat model of post-inflammatory visceral hyperalgesia: a centrally mediated process. Pain. 2010;149:555-564.[PubMed] [DOI]
107.
Song GH, Leng PH, Gwee KA, Moochhala SM, Ho KY. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Gut. 2005;54:1402-1407.[PubMed] [DOI]
108.
Lu WZ, Gwee KA, Moochhalla S, Ho KY. Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2005;22:927-934.[PubMed] [DOI]
109.
Saha L, Malhotra S, Rana S, Bhasin D, Pandhi P. A preliminary study of melatonin in irritable bowel syndrome. J Clin Gastroenterol. 2007;41:29-32.[PubMed] [DOI]
110.
Lu WZ, Song GH, Gwee KA, Ho KY. The effects of melatonin on colonic transit time in normal controls and IBS patients. Dig Dis Sci. 2009;54:1087-1093.[PubMed] [DOI]
111.
Jan JE, Freeman RD. Re: Mann--melatonin for ulcerative colitis?. Am J Gastroenterol. 2003;98:1446.[PubMed]
112.
Mann S. Melatonin for ulcerative colitis?. Am J Gastroenterol. 2003;98:232-233.[PubMed] [DOI]
113.
Maldonado MD, Calvo JR. Melatonin usage in ulcerative colitis: a case report. J Pineal Res. 2008;45:339-340.[PubMed] [DOI]
114.
Calvo JR, Guerrero JM, Osuna C, Molinero P, Carrillo-Vico A. Melatonin triggers Crohn's disease symptoms. J Pineal Res. 2002;32:277-278.[PubMed] [DOI]
115.
Poon AM, Mak AS, Luk HT. Melatonin and 2[125I]iodomelatonin binding sites in the human colon. Endocr Res. 1996;22:77-94.[PubMed] [DOI]
116.
Kos-Kudla B, Ostrowska Z, Kozlowski A, Marek B, Ciesielska-Kopacz N, Kudla M, Kajdaniuk D, Strzelczyk J, Staszewicz P. Circadian rhythm of melatonin in patients with colorectal carcinoma. Neuro Endocrinol Lett. 2002;23:239-242.[PubMed]
117.
Hrushesky WJ, Grutsch J, Wood P, Yang X, Oh EY, Ansell C, Kidder S, Ferrans C, Quiton DF, Reynolds J. Circadian clock manipulation for cancer prevention and control and the relief of cancer symptoms. Integr Cancer Ther. 2009;8:387-397.[PubMed] [DOI]
118.
Dalio MB, Haikel Júnior LF, Dalio RB, Pinto AP, Silva JC, Vespúcio MV, Guimarães MA, Garcia SB. A study of the effects of pinealectomy on intestinal cell proliferation in infant newborn rats. Acta Cir Bras. 2006;21:16-20.[PubMed] [DOI]
119.
Callaghan BD. The long-term effect of pinealectomy on the crypts of the rat gastrointestinal tract. J Pineal Res. 1995;18:191-196.[PubMed] [DOI]
120.
Lissoni P, Rovelli F, Malugani F, Bucovec R, Conti A, Maestroni GJ. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuro Endocrinol Lett. 2001;22:45-47.[PubMed]
121.
Blask DE, Wilson ST, Zalatan F. Physiological melatonin inhibition of human breast cancer cell growth in vitro: evidence for a glutathione-mediated pathway. Cancer Res. 1997;57:1909-1914.[PubMed]
122.
Farriol M, Venereo Y, Orta X, Castellanos JM, Segovia-Silvestre T. In vitro effects of melatonin on cell proliferation in a colon adenocarcinoma line. J Appl Toxicol. 2000;20:21-24.[PubMed]
123.
Panzer A, Viljoen M. The validity of melatonin as an oncostatic agent. J Pineal Res. 1997;22:184-202.[PubMed] [DOI]
124.
Wenzel U, Nickel A, Daniel H. Melatonin potentiates flavone-induced apoptosis in human colon cancer cells by increasing the level of glycolytic end products. Int J Cancer. 2005;116:236-242.[PubMed] [DOI]
125.
García-Navarro A, González-Puga C, Escames G, López LC, López A, López-Cantarero M, Camacho E, Espinosa A, Gallo MA, Acuña-Castroviejo D. Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture. J Pineal Res. 2007;43:195-205.[PubMed] [DOI]
126.
Karasek M, Carrillo-Vico A, Guerrero JM, Winczyk K, Pawlikowski M. Expression of melatonin MT(1) and MT(2) receptors, and ROR alpha(1) receptor in transplantable murine Colon 38 cancer. Neuro Endocrinol Lett. 2002;23 Suppl 1:55-60.[PubMed]
127.
Winczyk K, Fuss-Chmielewska J, Lawnicka H, Pawlikowski M, Karasek M. Luzindole but not 4-phenyl-2- propionamidotetralin (4P-PDOT) diminishes the inhibitory effect of melatonin on murine Colon 38 cancer growth in vitro. Neuro Endocrinol Lett. 2009;30:657-662.[PubMed]
128.
Ravindra T, Lakshmi NK, Ahuja YR. Melatonin in pathogenesis and therapy of cancer. Indian J Med Sci. 2006;60:523-535.[PubMed] [DOI]
129.
Tanaka T, Yasui Y, Tanaka M, Tanaka T, Oyama T, Rahman KM. Melatonin suppresses AOM/DSS-induced large bowel oncogenesis in rats. Chem Biol Interact. 2009;177:128-136.[PubMed] [DOI]
130.
Miller SC, Pandi-Perumal SR, Esquifino AI, Cardinali DP, Maestroni GJ. The role of melatonin in immuno-enhancement: potential application in cancer. Int J Exp Pathol. 2006;87:81-87.[PubMed] [DOI]
131.
Martins E, Fernandes LC, Bartol I, Cipolla-Neto J, Costa Rosa LF. The effect of melatonin chronic treatment upon macrophage and lymphocyte metabolism and function in Walker-256 tumour-bearing rats. J Neuroimmunol. 1998;82:81-89.[PubMed] [DOI]
132.
Lissoni P, Barni S, Tancini G, Rovelli F, Ardizzoia A, Conti A, Maestroni GJ. A study of the mechanisms involved in the immunostimulatory action of the pineal hormone in cancer patients. Oncology. 1993;50:399-402.[PubMed] [DOI]
133.
Lissoni P. Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms. Pathol Biol (Paris). 2007;55:201-204.[PubMed] [DOI]
134.
Lissoni P, Barni S, Mandalà M, Ardizzoia A, Paolorossi F, Vaghi M, Longarini R, Malugani F, Tancini G. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer. 1999;35:1688-1692.[PubMed] [DOI]
135.
Cerea G, Vaghi M, Ardizzoia A, Villa S, Bucovec R, Mengo S, Gardani G, Tancini G, Lissoni P. Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations. Anticancer Res. 2003;23:1951-1954.[PubMed]
136.
Lissoni P, Barni S, Tancini G, Ardizzoia A, Ricci G, Aldeghi R, Brivio F, Tisi E, Rovelli F, Rescaldani R. A randomised study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma. Br J Cancer. 1994;69:196-199.[PubMed] [DOI]
137.
Barni S, Lissoni P, Cazzaniga M, Ardizzoia A, Meregalli S, Fossati V, Fumagalli L, Brivio F, Tancini G. A randomized study of low-dose subcutaneous interleukin-2 plus melatonin versus supportive care alone in metastatic colorectal cancer patients progressing under 5-fluorouracil and folates. Oncology. 1995;52:243-245.[PubMed] [DOI]
138.
Lissoni P, Giani L, Zerbini S, Trabattoni P, Rovelli F. Biotherapy with the pineal immunomodulating hormone melatonin versus melatonin plus aloe vera in untreatable advanced solid neoplasms. Nat Immun. 1998;16:27-33.[PubMed] [DOI]
139.
Persson C, Glimelius B, Rönnelid J, Nygren P. Impact of fish oil and melatonin on cachexia in patients with advanced gastrointestinal cancer: a randomized pilot study. Nutrition. 2005;21:170-178.[PubMed] [DOI]
140.
Lissoni P, Rovelli F, Brivio F, Fumagalli L, Brera G. A study of immunoendocrine strategies with pineal indoles and interleukin-2 to prevent radiotherapy-induced lymphocytopenia in cancer patients. In Vivo. 2008;22:397-400.[PubMed]