Possible prolactin-mediated effects of melatonin on gonadotropin secretion in the rat

Melatonin administration to pituitary-grafted male and female rats resulted in a marked decrease of previously high plasma prolactin levels, while an increase in prolactin levels was observed in sham-operated controls. The latter effect was significant only in males. Treatment with melatonin did not modify basal LH hormone levels or LH responses to luteinizing hormone-releasing hormone (LHRH) in sham-operated rats of either sex. However, in pituitary-grafted females, melatonin increased both basal and LHRH-stimulated LH levels towards values recorded in sham-operated controls. No effects on basal LH levels were detected in grafted males under melatonin treatment, but the response of LH to LHRH was markedly increased and no longer differed from the values measured in sham-operated control animals pretreated with saline. Melatonin did not affect follicle stimulating hormone (FSH) levels except for an increase in FSH response to LHRH in grafted females. These findings suggest the existence of sex-dependent effects of melatonin on LH and FSH secretions. These effects of melatonin may be mediated by the different plasma prolactin levels in pituitary-grafted and sham-operated rats.     

Feasibility and functionality of OROS melatonin in healthy subjects.

OROS (melatonin), an oral osmotic system for controlled drug delivery, was evaluated in an open-label, two-way crossover study to test the feasibility of continuous overnight melatonin delivery. Twelve healthy subjects with no sleep disorders, ranging from 60 to 73 years of age, were enrolled in the study. Two doses of melatonin (1 x 110 micrograms and 4 x 110 micrograms) were administered on two separate occasions. Endogenous baseline nighttime serum melatonin concentrations were measured the night before each treatment. Following treatment at 2100 hours, the lights were extinguished at 2200 hours and remained so, except during blood sample collection, which was performed under dim light (< 50 lux) at specified times. Serum samples were analyzed for melatonin by an LC/MS/MS method. In addition, safety measurements such as vitals and serum samples for endocrine functions were measured both prior to and after melatonin dosing. The serum melatonin concentration profile following OROS (melatonin) dosing mimicked the normal endogenous serum melatonin concentration-time profile. The mean maximal melatonin concentration occurred at 3 a.m. The mean AUCs of endogenous melatonin before the two treatment days were 248 and 234 pg.h/mL, respectively. Serum concentrations of melatonin corrected for endogenous production increased proportionally with dose, with AUCs of 288 and 1069 pg.h/mL, respectively. Deconvolution of the serum concentration data showed good correlation between the in vitro amount released and the in vivo amount absorbed, suggesting continuous absorption throughout the gastrointestinal tract. Less than 5% residual content was observed in the recovered OROS system. Minimal changes in serum hormone concentrations (luteinizing hormone, follicular stimulating hormone, and prolactin) and no serious adverse events were observed following OROS treatment in these subjects. Delivery of melatonin with OROS formulation may result in a physiologic nocturnal profile in elderly subjects.     

Section Review Oncologic,Endocrine & Metabolic: Melatonin related to health promotion and biological function

Melatonin is the main hormone secreted by the pineal gland. Bright light inhibits melatonin synthesis, so the amount of hormone present in the blood increases dramatically at night. Due to its sedative effects, melatonin has been linked to quality of sleep and may be used as a sleeping agent. In addition, there seems to be some correlation between melatonin levels and seasonal affective disorder (SAD). In high doses, melatonin is able to suppress ovulation, making it a promising birth control agent. Melatonin had been accepted as a regulator for many systems, including the immune system. For this reason, melatonin is being looked at as a supplement in the treatment of acquired immunodeficiency syndrome (AIDS) and cancer. Melatonin may be helpful to the body because of its antioxidant qualities and may reduce the risk of heart disease.     

Effects of P-chlorophenylalanine on pineal and endocrine function in the rat

This study attempted to determine whether brain serotonin (5-HT), which is altered by melatonin administration, is involved in mediating the effects of melatonin on basal endocrine function. Pineal melatonin levels, serum N-acetylserotonin (NAS) levels, adrenocortical activity, and other endocrine parameters were measured following 5-HT depletion by p-chlorophenylalanine (p-CPA) together with either pineal stimulation by blinding or blinding plus pinealectomy. Blinding increased pineal melatonin levels in both saline and p-CPA treated animals. P-CPA treatment increased adrenal weights and morning plasma corticosterone levels in both blinded and blinded-pinealectomized animals. Conversely, p-CPA depressed pineal melatonin levels and serum NAS but elevated morning plasma corticosterone levels in sighted controls. P-CPA also decreased plasma prolactin and growth hormone levels in intact animals. These findings suggest that 5-HT inhibits morning corticosterone secretion and stimulates prolactin and growth hormone release. In addition, melatonin and serotonin may function independently in regulating adrenocortical function, while melatonin's effect is superceded by that of serotonin.     

Pineal hormone melatonin: solubilization studies in model aqueous gastrointestinal environments

In view of the variable oral absorption, short biological half-life and extensive first pass metabolism of the pineal hormone melatonin, an investigation of its solubilization profile in modified aqueous media is described. Four readily available surfactants were examined with respect to their ability to enhance the solubility of melatonin under simulated physiological conditions. The most effective surfactant was found to be the sodium salt of dioctyl sulfosuccinate (DSS), which augmented the aqueous solubility of the hormone by 23%. This is attributed to a favourable stereoelectronic interaction between DSS and the nucleus of melatonin, which seems to be independent of the pH of the dissolution medium. A noteworthy synergistic effect in the aqueous solubilization of the hormone occurs when a 1:2 DSS-sodium dodecyl sulphate mixture is used.     

Opposite effects of zinc and melatonin on thyroid hormones in rats

The present study was conducted to investigate how thyroid function in rats is affected by administration of 3 mg per kg per day of zinc and/or melatonin. The study was conducted with 40 Sprague-Dawley adult male rats equally divided into four groups: 1 (controls), 2 (zinc-only), 3 (melatonin-only) and 4 (zinc- and melatonin-supplemented). The supplementation was continued for 4 weeks after which the animals were sacrificed and plasma samples were obtained for determination of zinc, melatonin, free- and total triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH) levels. The free T3, T4 and TSH levels were lower in the melatonin group than in all other groups (P<0.01), while free- and total T3 levels were higher in the zinc group (P<0.01). The group that received zinc and melatonin combined had free thyroid hormone levels higher than the only melatonin group. These results show that melatonin has a thyroid function suppressing action, just the opposite to the actions of zinc. When zinc is administered along with melatonin, its thyroid function suppression is diminished.     

Melatonin receptors: potential targets for central nervous system disorders

The pineal hormone melatonin has become the subject of considerable speculation in both the scientific and lay press. Media coverage, coupled with scientific interest fuelled by the recent molecular cloning of a family of melatonin receptors, has led to a renaissance in melatonin research. While numerous physiological effects have been attributed to melatonin, the lack of selective agonists and antagonists for individual melatonin receptor subtypes has hampered progress towards the elucidation of the roles of these receptors. This review focuses on the molecular and pharmacological characterisation of melatonin receptors, the possible clinical utility of melatonin receptor ligands, and the progress towards the identification of selective ligands for these receptors.     

褪黑素能类药物治疗睡眠障碍的研究进展

睡眠障碍治疗困难,需要开发新的、更好的睡眠治疗药。褪黑素是松果体分泌的一种神经内分泌激素,能通过特异受体介导,发挥调节昼夜节律和睡眠的作用。研发褪黑素能类药物（包括褪黑素、褪黑素类似物/替代品、受体激动剂）治疗睡眠障碍具有重要意义,本文综述了褪黑素以及雷美尔通、特斯美尔通、阿戈美拉汀等褪黑素受体激动剂治疗睡眠障碍的研究进展。     

Significance of melatonin for the activity and the pharmacological regulation of the cardiovascular system

The data about pineal hormone melatonin influence on cardiovascular system of the people and animals were summarized. There are some evidences on therapeutic features of melatonin in treatment of arterial hypertension and cardiac ischemic disease.     

Melatonin improves memory acquisition under stress independent of stress hormone release

RATIONALE: Animal studies suggest that the pineal hormone melatonin influences basal stress hormone levels and dampens hormone reactivity to stress. OBJECTIVES: We investigated whether melatonin also has a suppressive effect on stress-induced catecholamine and cortisol release in humans. As stress hormones affect memory processing, we further examined a possible accompanying modulation of memory function. MATERIALS AND METHODS: Fifty healthy young men received a single oral dose of either 3 mg melatonin (n = 27) or placebo medication (n = 23). One hour later, they were exposed to a standardized psychosocial laboratory stressor (Trier Social Stress Test). During stress, subjects encoded objects distributed in the test room, for which memory was assessed a day later ("memory encoding under stress"). Fifteen minutes following stress, memory retrieval for words learnt the day before was tested ("memory retrieval after stress"). Plasma epinephrine and norepinephrine levels, salivary free cortisol levels and psychological responses (attention, wakefulness) were repeatedly measured before and after stress exposure. RESULTS: Melatonin specifically enhanced recognition memory accuracy of objects encoded under stress (p < 0.001). In contrast, 15 min after stress, when cortisol levels were highest, retrieval of memories acquired the day before was not influenced by melatonin. Moreover, melatonin did not influence stress-induced elevation of catecholamine and cortisol levels which in turn did not correlate with the effects of melatonin on memory. CONCLUSIONS: The findings point to a primary action of melatonin on central nervous stimulus processing under conditions of stress and possibly on memory consolidation and exclude any substantial suppressive action of the substance on hormonal stress responses.     

Melatonin in experimental seizures and epilepsy

Although melatonin is approved only for the treatment of jet-lag syndrome and some types of insomnia, clinical data suggest that it is effective in the adjunctive therapy of osteoporosis, cataract, sepsis, neurodegenerative diseases, hypertension, and even cancer. Melatonin also modulates the electrical activity of neurons by reducing glutamatergic and enhancing GABA-ergic neurotransmission. The indoleamine may also be metabolized to kynurenic acid, an endogenous anticonvulsant. Finally, the hormone and its metabolites act as free radical scavengers and antioxidants. The vast majority of experimental data indicates anticonvulsant properties of the hormone. Melatonin inhibited audiogenic and electrical seizures, as well as reduced convulsions induced by pentetrazole, pilocarpine, L-cysteine and kainate. Only a few studies have shown direct or indirect proconvulsant effects of melatonin. For instance, melatonin enhanced low Mg2+-induced epileptiform activity in the hippocampus, whereas melatonin antagonists delayed the onset of pilocarpine-induced seizures. However, the relatively high doses of melatonin required to inhibit experimental seizures can induce some undesired effects (e.g., cognitive and motor impairment and decreased body temperature). In humans, melatonin may attenuate seizures, and it is most effective in the treatment of juvenile intractable epilepsy. Its additional benefits include improved physical, emotional, cognitive, and social functions. On the other hand, melatonin has been shown to induce electroencephalographic abnormalities in patients with temporal lobe epilepsy and increase seizure activity in neurologically disabled children. The hormone showed very low toxicity in clinical practice. The reported adverse effects (nightmares, hypotension, and sleep disorders) were rare and mild. However, more placebo-controlled, double-blind randomized clinical trials are needed to establish the usefulness of melatonin in the adjunctive treatment of epilepsy.     

Effect of prenatal melatonin exposure on gonadotropins and prolactin secretion in male and female rat pups.

We evaluated whether melatonin administration to pregnant rats during the final week of pregnancy affects prepubertal secretion of luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin in offspring. Melatonin was administered in the drinking water from day 14 to delivery. LH, FSH and prolactin concentrations were determined in plasma sampled from offspring between 5 and 30 days in the dark portion of the diurnal cycle. Administration of 2 or 20 microg/ml melatonin did not affect LH or FSH in male or female offspring. The 20-microg/ml dose caused a significant increase in prolactin in males and females at day 15. In contrast, melatonin, 2 or 20 microg/ml, decreased prolactin at days 25 and 30 in females and day 25 in males. Thus, prenatal melatonin exposure alters prolactin secretion, but not that of LH and FSH in infantile and prepubertal male and female rats.     

Studying the psychotropic activity of pineal hormone melatonin: original direction of our investigations. Twentieth anniversary of the melatonin study in the pharmacology department at the Stavropol medical academy

Results of a series of original investigations devoted to the antidepressant, anxiolytic, and nootropic activity of the pineal hormone melatonin are summarized. It is established that a decisive role in this activity belongs to the chronotropic properties of melatonin.     

New issues about melatonin and its effects on the digestive system

In human beings, melatonin is secreted in a cyclic way by the pineal gland, although it has been detected in other tissues. Synthesis of melatonin takes place in the pinealocyte. It depends on adrenergic stimulation, and its secretion is related to the photoperiod in a circadian model of low activity during light phase and high activity at night time. Former studies aimed to establish the mechanisms by which melatonin carries out its biological function, proved the existance of high affinity binding sites. However, melatonin can pass through the plasmatic membrane; this property suggested a possible activity of the hormone inside the cell trough activation of nuclear receptors. Moreover, melatonin can act by itself as a potent oxygen-free-radical scavenger, which renders it a very strong antioxidant. It is currently accepted that melatonin plays an important role in numerous physiological processes. The gastrointestinal tract of numerous animal species contains melatonin, which is synthesized essentially by intestinal enterochrommaffin cells. Some investigations have revealed that its liberation follows also a circadian rhythm, although its secretion pattern might be influenced by nutritional factors. Receptors for melatonin have been identified in the digestive system, therefore the indolamine might play a leading role in different aspects of the vast digestive physiopathology. The hormone may interact with receptors and subsequently stimulate the synthesis of gastroprotective hormones and also exerts a direct defense on the epithelium, enhances submucosal blood flow and prevents the damage induced by ischemia followed by reperfusion. Moreover, studies have shown that treatment with melatonin reduces the severity of the lesions induced by NSAIDs on gastric mucosa suggesting a beneficial role of melatonin in preventing this gastropathy related to antiinflammatories.     

Melatoninergic antidepressant valdoxan

Data on the pharmacological properties, mechanism of action, and clinical advantages of the new antidepressant drug valdoxan capable of selectively stimulating melatonin receptors are presented. The drug effect is compared to the action of epiphyseal hormone melatonin and traditional antidepressants.     

Melatonin and its physiological and therapeutic properties

Melatonin is a hormone produced mainly by the pineal gland in most vertebrate species, including humans. Recent metabolic, receptor and functional studies created a picture of the melatoninergic system(s) in living organisms, its organization, physiology and a role in some pathologic conditions. The melatoningenerating system is characterized by three basic features: (1) photosensitivity, (2) diurnal (or circadian) rhythmicity (with highest levels of melatonin production occurring at night in darkness), and (3) agerelated decline in its activity. Cyclic nocturnal increases of melatonin levels are proportional to the length of nights (or dark periods of an imposed lightdark cycle); the hormone thus conveys a photoperiodic message, and functions in an organism as an internal biochemical clock and calendar. Biological actions of melatonin are mediated via specific melatonin receptors, whose distribution in the body is uneven, yet with decisively highest density in the suprachiasmatic nuclei of the hypothalamus, pars tuberalis of the pituitary, and the retina (particularly in birds and lower vertebrates). Such a distribution of melatonin receptors suggests that the principal physiological role of the hormone is related to both chronobiology and modulation of the body hormonal milieu. This review surveys recent developments in the melatonin field, and summarizes current knowledge on the melatoninergic mechanisms, including the therapeutic aspect related to the hormone.     

Temporal oscillations of thyroid hormones in long term melatonin treated rats

Pharmacological doses of melatonin (0.5 mg/kg body wt. and 1.0 mg/kg body wt.) were chronically administered for 45 days to Wistar rats and 24 h rhythms of thyroid stimulating hormone (TSH), triiodothyronine (T3) tetraiodothyronine (T4) and melatonin were studied under semi-natural (LD12:12 h) conditions. Exogenous melatonin administration caused delays in the acrophases of T3, T4 and melatonin rhythm itself; whereas advances in the acrophases of TSH were observed, thus indicating chronic administration of melatonin could alter the characteristics of endocrine rhythms. Alterations in the amplitude and mesor values of these endocrine rhythms were also observed during melatonin administration. Exogenous administration of melatonin could influence the hormonal rhythms as a modulated internal zeitgeber and could simulate/mimic the conditions of altered photoperiod in the animals. Significant dose-dependent effects of melatonin were absent in the present study. It remains to be proven how exogenous administration of melatonin could influence these hormonal rhythms.     

褪黑素的神经保护作用

人体褪黑素是一种主要在松果体合成的激素，具有广泛的生理活性，主要包括调节生物节律，改善睡眠，以及抗氧化、免疫调节、抑制肿瘤等作用。介绍褪黑素的合成、代谢通路及其抗氧化、抗细胞凋亡等神经保护作用。阐述褪黑素的神经保护作用的临床意义。     

Effect of melatonin on memory, individual time perception, and anxiety in young people of different chronotype groups

Chronic administration of the pineal hormone melatonin in a low dose (0.75 mg) improved memory and optimized individual time perception in a group of young volunteers. These changes were pronounced even two weeks after termination of the drug administration. The expression of the melatonin effect was depended on the chronotype of humans tested.