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The Vertebrate Eye and Its Adaptive Radiation.

Melatonin, dubbed the hormone of darkness, is known to regulate a wide variety of physiological processes in mammals. This review describes well-defined functional responses mediated through activation of high-affinity MT1 and MT2 proteinteoupled receptors viewed as potential targets for drug discovery. MT1 melatonin receptors modulate neuronal firing, arterial vasoconstriction, cell proliferation in cancer cells, and reproductive and metabolic functions. Ativation of MT2 melatonin receptors phase shift circadian rhythms of neuronal firing in the suprachiasmatic nucleus, inhibit dopamine release in retina, induce vasodilation and inhibition of leukocyte rolling in arterial beds, and enhance immune responses. The melatonin-mediated responses elicited by activation of MT1 and MT2 native melatonin receptors are dependent on circadian time, duration and mode of exposure to endogenous or exogenous melatonin, and functional receptor sensitivity. Together, these studies underscore the importance of carefully linking each melatonin receptor type to specific functional responses in target tissues to facilitate the design and development of novel therapeutic agent.

Functional MT1 and MT2 melatonin receptors in mammals.

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.

Extrapineal melatonin: sources, regulation, and potential functions.

https://repositorio.uca.edu.ar/bitstream/123456789/1653/1/melatonin-pleiotropic-orchestrating-regulator-molecule.pdf

Melatonin—A pleiotropic, orchestrating regulator molecule

Molecular targets in cerebral ischemia for developing novel therapeutics.

Melatonin is a potent scavenger of free radicals and an indirect antioxidant. Recent studies have shown that melatonin possesses beneficial effects in experimental models of brain trauma and global cerebral ischemia. The effects of pretreatment with melatonin on volume of cerebral infarction were investigated in the present study. Adult male Sprague-Dawley rats were anesthetized with sodium pentobarbital to undergo right-sided endovascular middle cerebral artery occlusion (MCAO) for 3 hr. A single dose of melatonin (1.5, 5, 15, or 50 mg/kg in 1 mL normal saline) or its vehicle was given via an intraperitoneal injection at 0.5 hr before MCAO. Relative infarction volumes on day 3 after MCAO were significantly reduced in the groups treated with melatonin at 5 (mean +/- S.E.M., 15.7 +/- 2.5%) or 15 (21.4 +/- 3.1 %) mg/kg but not at 1.5 (30.6 +/- 3.5%) or 50 (26.7 +/- 2.8%) mg/ kg when compared with the vehicle group (33.9 +/- 3.5%). There was no significant difference in the arterial blood pressure (BP), heart rate (HR) and relative cerebral blood flow among the experimental groups. These results indicate that pretreatment with melatonin at a dose between 5 and 15 mg/kg protects against focal cerebral ischemia.

Pretreatment with melatonin reduces volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model.

Melatonin concentrations were determined in serum and 10 segments of the gastrointestinal tract (GIT) of 48 pigs (100 kg weight). The animals were fasted for 30 hr and then sacrificed 0, 1, 2, 5, 10, and 20 hr after refeeding. Peak amount of gastric digesta (2,428 g) and ileum digesta (850 g) were observed 1 hr and 5 hr, after refeeding, respectively. Conversely, colon content reached a minimal weight (726 g) at 2 hr after refeeding. Serum levels of melatonin increased from 3.4 pg/ml to 15.5 pg/ml (peak 5 hr after refeeding). Melatonin levels in GIT tissues before refeeding varied from 23.8 pg/g (stomach-fundus) to 62.1 pg/g (rectum). Increasingly higher levels of melatonin were detected in the distal segments of the GIT. Higher melatonin levels after refeeding were observed in most GIT tissues except the rectum. In most tissues, peak melatonin values were detected 5 hr after refeeding. A significant change in weight of digesta across time (P < 0.05) was detected in the stomach, ileum, and cecum. Similar changes in melatonin levels across time were found in most tissues except the esophagus, stomach (cardia and pylorus), and rectum. Adjacent GIT tissues exhibited similar (P < 0.05) melatonin levels. The GIT melatonin levels correlated best with the variation of digesta weight in the ileum. In addition, the increase of serum melatonin levels correlated best with the increase of GIT melatonin levels in the distal part of the GIT. Our results suggest that melatonin produced in the ileum, cecum, and colon may contribute significantly to the short-term increase of serum melatonin levels observed after refeeding.

Melatonin concentrations in serum and tissues of porcine gastrointestinal tract and their relationship to the intake and passage of food

Bubenik GA, Pang SF. The role of serotonin and megaton in gastrointestinal physiology: Ontogeny, regulation of food intake, and mutual serotonin-melatonin feedback. J. Pineal Res. 1994: 16: 91–99.



Abstract

Average levels of melatonin in the brain and the gastrointestinal (GIT) tissues of newborn mice declined dramatically during the first week postnatally. Food consumption increased considerably in mice bearing subcutaneous serotonin (5-HT) implants (2 mg). Melatonin implants (2 mg) also increased overall consumption but to a lesser degree. Both 5-HT and melatonin implants (2 mg) increased water content of mice fecal pellets, albeit the melatonin effect was less pronounced. Serotonin implants (2,4,6 mg/mouse) increased melatonin levels in brain, jejunum, ileum, and colon, but the effect was not dose-dependent. Intraperitoneally administered melatonin (5, 20 and 200 ug/mouse) elevated melatonin levels in brain and GIT tissues more than 100 times that of the controls, but the effect was not dose-dependent. In contrast, intraperitoneal administration of melatonin (5, 50, and 200 ug) in mice bearing a 5-HT implant (2 mg) resulted in only 3-7 times higher melatonin levels in the GIT as compared to controls, and the brain levels of melatonin were actually lower. A feedback system between 5–HT and melatonin is proposed that regulates appetite and digestive processes by endocrine as well as paracrine effects in both the brain and the GIT.

The role of serotonin and melatonin in gastrointestinal physiology: Ontogeny, regulation of food intake, and mutual serotonin‐melatonin feedback

In order to investigate the effect of food deprivation on the levels of indoles in the brain and the gastrointestinal tissues, we have determined tissue levels of tryptophan (TRP), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and melatonin in the brain and the gastrointestinal tract (GIT) of mice on ad libitum diet as well as in mice deprived of food for 24 and 48 hr. The reduction of food intake 1) had no effect on TRP levels in the brain, but increased TRP concentrations in the stomach and the gut, especially in the colon; 2) decreased 5-HT levels in the brain, but increased values in the stomach and the intestines; 3) decreased 5-HIAA levels in the brain, but increased them in the stomach and the intestines; 4) did not change 5-HT conversion to 5-HIAA in the brain, stomach, and the jejunum, but increased the conversion in the ileum and colon and; 5) increased melatonin levels in all tissues investigated, particularly in the stomach and the brain. The changes of indole levels induced by food deprivation were compared to their known function in the brain and the individual segments of the GIT. A possible serotonin-melatonin antagonism in the brain and GIT function is considered.

The effect of food deprivation on brain and gastrointestinal tissue levels of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin.

Circadian levels of melatonin were determined in the hepatic portal vein, cranial vena cava, and the lower aorta of ten juvenile pigs. Blood was sampled every hour for a total of 24 hr via temporary cannulas introduced into blood vessels under anesthesia. No peak levels of melatonin were found in the mid-scotophase, but hepatic portal concentrations peaked at 06.00 hr. Overall levels of melatonin were highest in the hepatic portal vein (range 35-65 pg/mL), followed by an artery (range 30-55 pg/mL) and the vena cava (range 25-35 pg/mL). Levels of melatonin exhibit strong variation between individual pigs, but generally the average levels from all three sources follow each other's time course. However, on occasion, melatonin levels in the hepatic portal vein varied independently from the levels in the vena cava. Large portal peaks were usually preceded by a feeding period and were associated with a subsequent period of sleep. The data indicate that: 1) there is no clear circadian rhythm of melatonin in the peripheral blood of pigs, 2) relatively little melatonin is metabolized during the first liver passage, 3) food intake may elevate melatonin levels in the hepatic portal vein, and 4) increased levels of melatonin originated in the gastrointestinal tract may induce sleep.

Shiu-Fun Pang

Papers

Pretreatment with melatonin reduces volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model.

Melatonin concentrations in serum and tissues of porcine gastrointestinal tract and their relationship to the intake and passage of food

The role of serotonin and melatonin in gastrointestinal physiology: Ontogeny, regulation of food intake, and mutual serotonin‐melatonin feedback

The effect of food deprivation on brain and gastrointestinal tissue levels of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin.

Circadian variation of portal, arterial and venous blood levels of melatonin in pigs and its relationship to food intake and sleep