Short-term Melatonin Treatment Research Articles

Histopathological changes in androgenized ovaries are recovered by melatonin treatment.

Nandrolone decanoate (ND) is a synthetic steroid, which promotes adverse effects on the ovarian tissue, and melatonin (MLT) exhibits a number of beneficial properties in the reproductive system. This study evaluated the general features of the ovarian tissue and the immunoexpression of sex steroid receptors in ND-treated rats that were submitted to short-term melatonin treatment. Adult rats received mineral oil (control group) and ND at doses of 7.5 mg/kg for 15 days (ND-treated group). The treatment with MLT (10mg/kg for 7 days) was given alone, before or in combination with ND. All ND-treated animals showed persistent dioestrus. In the androgenized groups that received MLT, ovarian morphology and size, and the number/area of corpora lutea were recovered. The number of healthy and atretic follicles was recovered when MLT was administered prior to ND; this was similar to the ovaries of control and MLT groups. There was a decrease in estrogen receptors immunostaining in the follicles of androgenized rats that were treated with MLT, and pretreatment with MLT reduced the expression of androgen receptor in atretic follicles and corpora lutea, when compared with ND-treated group. We conclude that MLT treatment recovered the histopathological aspects of the androgenized ovaries, and MLT pretreatment was the most effective.

Role of melatonin in glucose uptake by cardiomyocytes from insulin-resistant Wistar rats.

SummaryAimMelatonin supplementation reduces insulin resistance and protects the heart in obese rats. However, its role in myocardial glucose uptake remains unknown. This study investigated the effect of short-term melatonin treatment on glucose uptake by cardiomyocytes isolated from obese and insulin-resistant rats.MethodsCardiomyocytes were isolated from obese rats fed a high-calorie diet for 16 to 23 weeks, their age-matched controls, as well as young control rats aged four to eight weeks. After incubation with melatonin with or without insulin, glucose uptake was initiated by the addition of 2-deoxy-D-[3H] glucose and measured after 30 minutes. Additional control and obese rats received melatonin in the drinking water (4 mg/kg/day) for the last six weeks of feeding (20 weeks) and glucose uptake was determined in isolated cardiomyocytes after incubation with insulin. Intraperitoneal glucose tolerance and biometric parameters were also measured.ResultsObese rats (fed for more than 20 weeks) developed glucose intolerance. Cardiomyocytes isolated from these obese rats had a reduced response to insulin-stimulated glucose uptake (ISGU) (p < 0.05). Melatonin administration in vitro had no effect on glucose uptake per se. However, it increased ISGU by cardiomyocytes from the young rats (p < 0.05), while having no effect on ISGU by cardiomyocytes from the older control and obese groups. Melatonin in vivo had no significant effect on glucose tolerance, but it increased basal (p < 0.05) and ISGU by cardiomyocytes from the obese rats (50.1 ± 1.7 vs 32.1 ± 5.1 pmol/mg protein/30 min, p < 0.01).ConclusionThese data suggest that short-term melatonin treatment in vivo but not in vitro improved glucose uptake and insulin responsiveness of cardiomyocytes in obesity and insulin-resistance states.

Gender-related Histological Changes in the Thymus Gland After Pinealectomy and Short-term Melatonin Treatment in Rats.

ObjectivesThe aim of this study was to investigate the effects of pinealectomy and melatonin treatment on the rat thymus gland characteristics, taking into consideration possible gender differences.Materials and methodsThirty adult Wistar rats of both sexes were divided into three groups. Group C and group PX served as control groups and included sham-pinealectomized and pinealectomized animals that were treated with 10% ethanol solution (0,1ml/daily, subcutaneous). Animals from third group (group PXM) underwent pinealectomy and seven days after surgery started receiving melatonin dissolved in 10% ethanol solution (3mg/kg/daily, subcutaneous). All animals were treated for 4 weeks.ResultsVolume density of the thymus cortex showed statistically significant (p<0,05) decrease while the volume density of the thymus medulla was increased in the pinealectomized compared to the sham-pinealectomized female rats. Numerical density of macrophages as well as the distribution of blood vessels showed no gender differences. The numerical density of lymphocytes was statistically significantly decreased in female in comparison to the male pinealectomized rats. Melatonin treatment was proved to cause reverse effects in the sense that the results from the melatonin treated group corresponded to the results obtained from the control group of animals.ConclusionThe results of this study suggest that the pinealectomy causes gender-related changes in the rat thymus. Short-term melatonin treatment showed reverse effect, equally in both sexes.

Abstract 18554: Short-term Melatonin Treatment Protects the Hearts of Obese Rats Independent of Changes in Body Weight and Visceral Fat Mass

Melatonin treatment has been shown to prevent the harmful effects of diet-induced obesity and reduce myocardial susceptibility to ischaemia-reperfusion injury (IRI) when administered from the onset of obesity. However, the exact mechanism whereby it exerts its beneficial actions on the heart in obesity and insulin resistance is unknown. In this study we investigated the effects of relatively short-term melatonin treatment on the heart in a rat model of diet-induced obesity. Control (C) and diet-induced obese (D) Wistar rats (fed for 20 weeks (wks)) were divided into 3 groups receiving drinking water with or without melatonin (4mg/kg/day) for the last 6 or 3 wks of experimentation. Isolated hearts were perfused in the working mode, subjected to regional (35min) or global ischaemia (15min) and reperfusion (2h); others were non-perfused (baseline). Myocardial infarct sizes as well as baseline and post-ischaemic activation of PKB/Akt, ERK42/44, GSK-3β and STAT-3 were determined. Blood was collected for study of metabolic parameters. Diet-induced obesity caused significant increases in body weight gain (14.5%), visceral adiposity (70.3%), fasting blood glucose (20%), serum insulin (55.6%) and triglyceride (84.2%) levels with a concomitant increase in post-ischaemic myocardial infarct size (41%) and a reduced cardiac output (12.7%). Melatonin treatment (both 3 and 6 wks) decreased serum insulin levels and the HOMA-index in the D group only (3 wks % reduction: 39%; 47.2%, p&lt;0.05 vs untreated D respectively) with no effect on body weight gain, visceral adiposity, serum triglycerides and glucose levels. It also increased serum adiponectin levels in the D group (113% p&lt;0.05 vs untreated D), reduced myocardial infarct sizes in both groups (3 wks %reduction: C 42.4%; D 61.6%) and activated baseline myocardial STAT-3, PKB/Akt, ERK42/44 and GSK-3β after 10 min reperfusion. Short-term melatonin administration to obese and insulin resistant rats reduced insulin resistance and protected the heart against ex vivo myocardial IRI independently of body weight gain and visceral adiposity. Melatonin-induced cardioprotection was associated with concomitant activation of the RISK and SAFE pathways.

Short-term melatonin consumption protects the heart of obese rats independent of body weight change and visceral adiposity.

Chronic melatonin treatment has been shown to prevent the harmful effects of diet-induced obesity and reduce myocardial susceptibility to ischaemia-reperfusion injury (IRI). However, the exact mechanism whereby it exerts its beneficial actions on the heart in obesity/insulin resistance remains unknown. Herein, we investigated the effects of relatively short-term melatonin treatment on the heart in a rat model of diet-induced obesity. Control and diet-induced obese Wistar rats (fed a high calorie diet for 20 wk) were each subdivided into three groups receiving drinking water with or without melatonin (4 mg/kg/day) for the last 6 or 3 wk of experimentation. A number of isolated hearts were perfused in the working mode, subjected to regional or global ischaemia-reperfusion; others were nonperfused. Metabolic parameters, myocardial infarct sizes (IFS), baseline and postischaemic activation of PKB/Akt, ERK42/44, GSK-3β and STAT-3 were determined. Diet-induced obesity caused increases in body weight gain, visceral adiposity, fasting blood glucose, serum insulin and triglyceride (TG) levels with a concomitant cardiac hypertrophy, large postischaemic myocardial IFSs and a reduced cardiac output. Melatonin treatment (3 and 6 wk) decreased serum insulin levels and the HOMA index (P < 0.05) with no effect on weight gain (after 3 wk), visceral adiposity, serum TG and glucose levels. It increased serum adiponectin levels, reduced myocardial IFSs in both groups and activated baseline myocardial STAT-3 and PKB/Akt, ERK42/44 and GSK-3β during reperfusion. Overall, short-term melatonin administration to obese/insulin resistant rats reduced insulin resistance and protected the heart against ex vivo myocardial IRI independently of body weight change and visceral adiposity.

Melatonin for prevention of metabolic side-effects of olanzapine in patients with first-episode schizophrenia: Randomized double-blind placebo-controlled study

We aimed to determine the efficacy of melatonin 3 mg/day in prevention of olanzapine-induced metabolic side-effects. In a randomized double-blind placebo-controlled study, 48 patients with first-episode schizophrenia who were eligible for olanzapine treatment, were randomly assigned to olanzapine plus either melatonin 3 mg/day or matched placebo for eight weeks. Anthropometric and metabolic parameters as well as psychiatric symptoms using The Positive and Negative Syndrome Scale (PANSS) were assessed at baseline, week 4, and 8. Primary outcome measure was the change from baseline in weight at week 8. Data were analyzed using t-test, Mann–Whitney U test, and mixed-effects model. Thirty-six patients had at least one post-baseline measurement. At week eight, melatonin was associated with significantly less weight gain [mean difference (MD) = 3.2 kg, P = 0.023], increase in waist circumference [MD = 2.83 cm, P = 0.041] and triglyceride concentration [MD = 62 mg/dl, P = 0.090 (nearly significant)] than the placebo. Changes in cholesterol, insulin, and blood sugar concentrations did not differ significantly between the two groups. Patients in the melatonin group experienced significantly more reduction in their PANSS scores [MD = 12.9 points, P = 0.014] than the placebo group. No serious adverse events were reported. To summarize, in patients treated with olanzapine, short-term melatonin treatment attenuates weight gain, abdominal obesity, and hypertriglyceridemia. It might also provide additional benefit for treatment of psychosis. The study was registered in the ClinicalTrials.gov (Registration number: NCT01593774).

Photoperiodic induced melatonin regulates immunity and expression pattern of melatonin receptor MT1 in spleen and bone marrow mononuclear cells of male golden hamster

The pineal gland transduces day length information into chemical signal of melatonin that ultimately translates photic stimulus into season-specific immune responses to promote survival of individual from incidence of opportunistic diseases. To date, the immune adjustments being a result of photoperiodic exposures for any nocturnal seasonally breeding rodent have not been systematically examined. Therefore, we evaluated the humoral and cell mediated immune responses of photoperiodically entrained male golden hamsters. Short day induced melatonin increased the immune parameters such as spleen mass, total leukocyte (TLC) and lymphocyte count (LC), proliferation of splenocytes, peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMNCs) along with serum IL-2 and anti-Keyhole Limpet Hemocyanin (KLH) IgG production when compared with long day experienced hamsters. Short term melatonin treatment (for two weeks) to long day hamsters enhanced to some extent the proliferation of splenocytes, PBMC and TLC/LC. We also localized the melatonin membrane receptor MT1 in spleen and BMMNCs that strongly supported our western blot analysis for the expression of MT1 in spleen suggesting that different photoperiodically induced circulatory melatonin is responsible for the immunomodulation. Therefore, photoperiod can influence the peripheral melatonin level to improve immune responses of hamsters according to season for better survival.

Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: Protection by melatonin and cranberry flavonoids

In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8g/kg body weight, single injection) or chronic (1.6g/ kg body weight, 30days, biweekly injections) carbon tetrachloride – induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats.Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, p<0.05). Short-term melatonin treatment (10mg/kg, three times) of rats did not reduce the degree of toxic mitochondrial dysfunction but decreased the enhanced NO production.After 30-day chronic intoxication, no significant change in the respiratory activity of liver mitochondria was observed, despite marked changes in the redox-balance of mitochondria. The activities of the mitochondrial enzymes, succinate dehydrogenase and glutathione peroxidase, as well as that of cytoplasmic catalase in liver cells were inhibited significantly. Mitochondria isolated from the livers of the rats chronically treated with CCl4 displayed obvious irreversible impairments. Long-term melatonin administration (10mg/kg, 30days, daily) to chronically intoxicated rats diminished the toxic effects of CCl4, reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10mg/kg) plus succinate (50mg/kg) plus cranberry flavonoids (7mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage.

A randomized controlled trial of oral melatonin supplementation and breast cancer biomarkers

We examined compliance with and the effects of melatonin supplementation on breast cancer biomarkers (estradiol, insulin-like growth factor I (IGF-1), insulin-like growth factor-binding protein 3 (IGFBP-3), and the IGF-1/IGFBP-3 ratio) in postmenopausal breast cancer survivors. In a double-blind, placebo-controlled study, postmenopausal women with a prior history of stages 0-III breast cancer who had completed active cancer treatment (including hormonal therapy) were randomly assigned to either 3 mg oral melatonin (n = 48) or placebo daily for 4 months. Plasma samples were collected at baseline and after the completion of the intervention. The primary endpoints were compliance and change in estradiol and IGF-1/IGFBP-3 levels. Ninety-five women were randomized (48 to melatonin and 47 to placebo). Eighty-six women (91%) completed the study and provided pre- and postintervention bloods. Melatonin was well tolerated without any grade 3/4 toxicity and compliance was high (89.5%). Overall, among postmenopausal women with a prior history of breast cancer, a 4-month course of 3 mg melatonin daily did not influence circulating estradiol, IGF-1, or IGFBP-3 levels. Compliance was comparable between the two groups. Short-term melatonin treatment did not influence the estradiol and IGF-1/IGBBP-3 levels. Effects of longer courses of melatonin among premenopausal women are unknown. Low baseline estradiol levels in our study population may have hindered the ability to detect any further estradiol-lowering effects of melatonin.

Termination of short term melatonin treatment in children with delayed Dim Light Melatonin Onset: Effects on sleep, health, behavior problems, and parenting stress

To investigate the effects of termination of short term melatonin treatment on sleep, health, behavior, and parenting stress in children with delayed Dim Light Melatonin Onset. Forty-one children (24 boys, 17 girls; mean age=9.43 years) entered melatonin treatment for 3 weeks and then discontinued treatment by first taking a half dose for 1 week and then stopping completely for another week. Sleep was measured with sleep diaries filled in by parents and with actometers worn by children. Analyses were conducted with linear mixed models. Sleep latency was longer during the stop week compared to the treatment weeks. Sleep start was later and actual sleep time was shorter during the half dose and stop weeks compared to the treatment weeks. Sleep efficiency deteriorated in the stop week. Dim Light Melatonin Onset was earlier after treatment, but this effect disappeared after the stop week. In addition to the effects on sleep, results from questionnaires completed by parents showed that melatonin treatment also had positive effects on children's health and behavior problems and parenting stress. While health deteriorated after treatment discontinuation, the effects on behavior problems and parenting stress remained. Behavior problems at baseline did not influence the effect of melatonin treatment. This study showed that complete termination of treatment after 4 weeks of melatonin use was too early. However, clinicians may advise a lower dose after a successful treatment trial of several weeks.

Exposure to short days, but not short‐term melatonin, enhances humoral immunity of male Syrian hamsters (Mesocricetus auratus)

Many non-tropical rodent species rely on photoperiod as the primary cue to co-ordinate seasonally appropriate changes in physiology and behavior. Among these seasonal changes, several rodent species (e.g. deer mice, prairie voles, Siberian hamsters) adjust immune function in response to changes in ambient day lengths. The goals of the present study were to examine the effects of photoperiod on immune function of Syrian hamsters (Mesocricetus auratus), and to determine the role of melatonin in mediating photoperiodic changes in immunity. In Experiment 1, male Syrian hamsters were housed in long (LD 14:10) or short days (LD 10:14) for 10 wk. In Experiment 2, hamsters were housed in long days and half of the animals were given 10 consecutive days of i.p. melatonin injections (15 microg) in the early evening, while the remaining animals received injections of the vehicle alone. After the respective experimental manipulations, animals were injected with the antigen, keyhole limpet hemocyanin (KLH), blood samples were obtained and anti-KLH IgG antibody production was assessed. In Experiment 1, short-day hamsters underwent gonadal regression and reduced serum testosterone as well as displayed increased humoral immune function compared with long-day animals. In Experiment 2, short-term melatonin treatment did not affect gonadal mass, testosterone or humoral immune function. These results confirm previous findings of photoperiodic changes in immunity in rodents and suggest that changes in humoral immunity are not due to short-term changes in melatonin.

Effect of long-term olanzapine treatment on weight change in schizophrenia

We aimed to determine the efficacy of melatonin 3 mg/day in prevention of olanzapine-induced metabolic side-effects. In a randomized double-blind placebo-controlled study, 48 patients with first-episode schizophrenia who were eligible for olanzapine treatment, were randomly assigned to olanzapine plus either melatonin 3 mg/day or matched placebo for eight weeks. Anthropometric and metabolic parameters as well as psychiatric symptoms using The Positive and Negative Syndrome Scale (PANSS) were assessed at baseline, week 4, and 8. Primary outcome measure was the change from baseline in weight at week 8. Data were analyzed using t-test, Mann–Whitney U test, and mixed-effects model. Thirty-six patients had at least one post-baseline measurement. At week eight, melatonin was associated with significantly less weight gain [mean difference (MD) = 3.2 kg, P = 0.023], increase in waist circumference [MD = 2.83 cm, P = 0.041] and triglyceride concentration [MD = 62 mg/dl, P = 0.090 (nearly significant)] than the placebo. Changes in cholesterol, insulin, and blood sugar concentrations did not differ significantly between the two groups. Patients in the melatonin group experienced significantly more reduction in their PANSS scores [MD = 12.9 points, P = 0.014] than the placebo group. No serious adverse events were reported. To summarize, in patients treated with olanzapine, short-term melatonin treatment attenuates weight gain, abdominal obesity, and hypertriglyceridemia. It might also provide additional benefit for treatment of psychosis. The study was registered in the ClinicalTrials.gov (Registration number: NCT01593774).

Influence of melatonin and oestradiol on the opioidergic regulation of LH and prolactin release in pony mares.

The aim of this study was to investigate the influence of oestradiol, melatonin and season on the opioid regulation of LH and prolactin release. Effects of the opioid antagonist naloxone (0.5 mg/kg) on LH and prolactin secretion were determined in ovariectomized pony mares. In experiment 1, mares in January (n = 6) were pretreated with oestradiol benzoate (5 micrograms/kg) for 20 days. In experiment 2, beginning in May, mares (n = 7) received melatonin (15 mg) for 15 days and subsequently a combination of melatonin plus oestradiol for 20 days. In experiment 3, beginning in May, mares (n = 6) were pretreated with oestradiol for 30 days, left untreated for 12 days and then given melatonin for 35 days. In all experiments the animals were injected with the opioid antagonist naloxone and saline on 2 consecutive days prior to treatment. In experiment 1, animals received naloxone and saline on days 10 and 11 and 20 and 21 following oestradiol treatment. In experiment 2, naloxone and saline were administered on days 15 and 16 following melatonin treatment and on days 10 and 11 and 20 and 21 of melatonin plus oestradiol treatment. In experiment 3, the animals received naloxone and saline on days 10 and 11, 20 and 21 and 30 and 31 of oestradiol treatment, prior to melatonin treatment and on days 15 and 16, 25 and 26 and 35 and 36 following melatonin. In January (experiment 1), naloxone evoked a significant (P < 0.05) LH release at all times, however the LH increment in response to naloxone increased during oestradiol pretreatment (P < 0.05). During the breeding season (experiments 2 and 3), naloxone induced a significant (P < 0.05) increase in plasma LH concentrations when mares had not been pretreated with oestradiol or melatonin and after oestradiol pretreatment. Basal LH concentrations and the LH increment in response to naloxone increased significantly (P < 0.05) during the 30-day oestradiol pretreatment. Melatonin decreased the naloxone-induced LH release and the LH release in response to naloxone and saline no longer differed after 25 and 35 days of melatonin pretreatment. When melatonin was given together with oestradiol for 20 days, again a significant (P < 0.05) LH release in response to naloxone occurred. Prolactin release was significantly (P < 0.05) increased by naloxone when mares had been pretreated with only melatonin. The opioid antagonist did not affect prolactin release in mares that had not been pretreated or received oestradiol either alone or in combination with melatonin. In conclusion, in long-term ovariectomized mares, opioids inhibit LH secretion independent from ovarian factors. This opioid inhibition of LH secretion is enhanced by oestradiol and reduced by melatonin. Although short-term melatonin treatment inactivates the opioid regulation of LH release, a prolonged influence of melatonin as occurs in winter does not prevent activation of the opioid system. This indicates that effects of melatonin on the opioid regulation of LH release change with time. An opioid inhibition of prolactin secretion is activated by melatonin given for 15-35 days but is lost under the prolonged influence of a short-day melatonin signal in winter.