Co-administration Of Melatonin Research Articles

Evaluating the Antidepressant-like Properties of Melatonin and Vitamin D3 Combination in Mice Subjected to Restraint Stress: Investigating the Involvement of Oxidative Stress

Background: Increased levels of oxidative stress are connected with depression. Due to the melatonin's antioxidant effects and Vitamin D3 (Vit D3)'s regulatory effect on the biosynthesis of neurotransmitters and neurotrophic factors, the present study investigated the possible protective effect of melatonin and Vit D3 combination on restraint stress-induced depression-like behaviors in mice. Methods: After being subjected to restraint stress, mice were divided into six groups using a randomization process. These groups included non-stressed and stressed vehicle-treated groups, as well as groups treated with Vit D3 (25 μg/kg/day), melatonin (10 mg/kg) or fluoxetine. A group also received a combination of both melatonin and Vit D3. The Forced Swimming Test (FST), and Open Field Test (OFT) were conducted to evaluate behavioural changes. The Malondialdehyde (MDA) level and Catalase (CAT), Superoxide Dismutase (SOD) activity, and ADP/ATP ratio were evaluated in the hippocampus of mice. Results: Restraint stress lengthened the immobility period in FST, while melatonin, Vit D3, and their combination all significantly reversed this impact. Co-administration of melatonin and Vit D3 was more effective than melatonin or Vit D3 administration alone at reducing immobility time. The exposure of mice to restraint stress has been linked to an elevation in the ADP/ATP ratio and oxidative stress in their hippocampus; however, these effects are reversed by the administration of melatonin and Vit D3 (10 mg/kg) alone or in combination. Melatonin and Vit D3 combination increased the hippocampus CAT activity compared with melatonin and Vit D3 alone. Conclusion: The current study's findings suggested that Vit D3 may enhance melatonin's potential as an antidepressant in FST.

The antioxidant and neuroprotective effects of melatonin on glyphosate-based herbicide-induced affective and cognitive impairments in rats

ABSTRACT Several studies have found that exposure to glyphosate-based herbicides (GBH) can lead to memory impairment and affective disorders. Oxidative stress (OS) is one of the mechanisms that can explain the neurotoxicity of GBH. Consequently, molecules with an antioxidant effect may have neuroprotective potential against GBH-related brain damage. In this work, we aim to evaluate the neuroprotective effect of melatonin (MEL) against affective and cognitive disorders caused by GBH. For this experiment, male Wistar rats received, during the peripubertal period, a daily administration of GBH (75 mg/kg) or GBH + MEL (4 mg/kg). At the end of the treatment, the open field, elevated plus maze, and forced swimming tests were used to explore anxiety levels and depression-like symptoms. While the Y-Maze and Morris Water Maze have been used to detect cognitive deficits, we also measured markers of OS, specifically catalase, nitric oxide, and lipid peroxidation, in the hippocampus and prefrontal cortex. Our results revealed that MEL reduces anxiety and depressive behavior, as well as the cognitive deficits caused by GBH. In addition, co-administration of MEL and GBH induced an improvement in the various markers of OS. The positive action of MEL against OS is therefore one of the mechanisms explaining its neuroprotective power against GBH.

The role of melatonin in preventing amiodarone-induced rat liver damage.

Long-term exposure to amiodarone, an antiarrhythmic drug, can induce different organ damage, including liver. Cell damage included by amiodarone is a consequence of mitochondrial damage, reactive oxygen species production, and cell energy depletion leading to programmed cell death. In the present study, hepatoprotective potential of neurohormone melatonin (50mg/kg/day) was evaluated in a chronic experimental model of liver damage induced by a 4-week application of amiodarone (70mg/kg/day). The obtained results indicate that amiodarone induces an increase in xanthine oxidase activity, as well as the content of the lipid and protein oxidatively modified products and p53 levels. Microscopic analysis further corroborated the biochemical findings revealing hepatocyte degeneration, apoptosis, and occasional necrosis, with the activation of Kupffer cells. Coadministration of melatonin and amiodaron prevented an increase in certain damage associated parameters, due to its multiple targets. In conclusion, the application of melatonin together with amiodarone prevented an increase in tissue oxidative damage parameters and moderately prevented liver cell apoptosis, indicating that the damage of hepatocytes provoked by amiodarone supersedes the protective properties of melatonin in a given dose.

Antidepressant-like Properties of Melatonin and Atorvastatin Combination following the Restraint Stress in Mice: A Study of Oxidative Stress Factors.

Antidepressant properties of melatonin and atorvastatin have been reported by clinical and experimental studies. Since both melatonin and atorvastatin possess antioxidant properties and considering the involvement of oxidative stress factors in depression, the aim of the present investigation was to study the possible role of oxidative stress factors in the antidepressant- like effect of melatonin and atorvastatin combination in mice forced swimming test. Following the induction of restraint stress, mice were randomly divided into eight groups including the non-stressed and stressed vehicle-treated groups, melatonin- and atorvastatintreated groups, a combination of melatonin and atorvastatin-treated group, and fluoxetineadministrated group. The open field test (OFT) and forced swimming test (FST) were carried out, and the hippocampus and prefrontal cortex were removed for the measurement of oxidative stress factors. Induction of restraint stress increased the immobility time in FST, and melatonin (10 mg/kg) significantly reduced it. Atorvastatin at both doses of 1 and 10 mg/kg could not alter the immobility time, significantly. Co-administration of melatonin and atorvastatin (10 mg/kg) exerted a significant antidepressant-like response and decreased the immobility time compared with melatonin or atorvastatin (10 mg/kg), alone. Induction of restraint stress elevated the malondialdehyde (MDA) levels in mice's hippocampus, while pretreatment of animals with atorvastatin (10 mg/kg) could reverse it. The co-administration of melatonin and atorvastatin (10 mg/kg) increased the cortical superoxide dismutase (SOD) activity compared with atorvastatin alone, but could not alter the catalase (CAT) activity. It is concluded that atorvastatin might augment the antidepressant-like properties of melatonin in FST.

Protective effect of hot peppers against amyloid β peptide and brain injury in AlCl3-induced Alzheimer's disease in rats.

This study investigated the therapeutic effect of red hot pepper (Capsicum annuum) methanolic extract in induced Alzheimer's disease using AlCl3 in male rats. Rats were injected with AlCl3 intraperitoneally (IP) daily for two months. Starting from the 2nd month of AlCl3, rats received, in addition, IP treatments with Capsicum extract (25 and 50 mg/kg) or saline. Other groups received only saline or Capsicum extract at 50 mg/kg for two months. Brain levels of reduced glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA) were determined. Additionally, paraoxonase-1 (PON-1) activity, interleukin-6 (IL-6), Aβ-peptide, and acetylcholinesterase (AChE) concentrations in the brain were measured. Behavioral testing included wire-hanging tests for neuromuscular strength and memory tests such as Y-maze and Morris water maze. Histopathology of the brain was also done. Compared with saline-treated rats, AlCl3 caused significant elevation of brain oxidative stress as GSH level and PON-1 activity were depleted along with MDA and NO level elevation in the brain. There were also significant increases in brain Aβ-peptide, IL-6, and AChE levels. Behavioral testing indicated that AlCl3 decreased neuromuscular strength and impaired memory performance. Capsicum extract given to AlCl3-treated rats significantly alleviated oxidative stress and decreased Aβ-peptide and IL-6 in the brain. It also improved grip strength and memory functioning and prevented neuronal degeneration in the cerebral cortex, hippocampus, and substantia nigra of AlCl3-treated rats. Short-term administration of ASA (50 mg/kg) has adverse effects on male reproductive function in mice. Co-administration of melatonin protects against ASA-induced impairment of male reproductive function by preventing the reduction in serum TAC and testosterone levels seen with ASA treatment alone.

Effect of miRs-17/20 on vasospasm in subarachnoid hemorrhage model of rats

Aim: To investigate the effects of melatonin and miRNA-17/20 administration on vasospasm and vascular damage on the bacillary artery in the Subarachnoid hemorrhage (SAH) model of rats.Methods: Rats were divided into 6 groups: Sham, SAH, SAH+NegmiRNA, SAH+MEL, SAH-miRs-17/20 group, SAH+MEL+miRs-17/20. For creating the SAH model the skin was cut with a vertical incision in the anterior region of the head.120 µL of fresh non-heparinized autologous arterial blood collected from the tail artery was injected into the prechiasmatic cistern under aseptic conditions. All steps in the Sham were the same as in the SAH group, except for blood injection. In the SAH+NegmiRs-17/20, miRs-17/20 miRNA Mimic-Negative Control#1 was administered 1 hour after SAH operation. In the SAH+MEL,10 mg/kg melatonin was administered intraperitoneally 1 hour after the SAH operation. In the SAH-miRs-17/20, mimic-miR-17 and mimic-miR-20 were given intranasally 1 hour after the SAH operation. In the SAH+MEL+miRs-17/20,intranasal mimic-miR-17 and intraperitoneal melatonin were administered 1 hour after the SAH operation. Brain samples, including the bacillary artery, were taken and subjected to routine tissue processing procedures. Vessel samples were evaluated and graded in histological sections stained with the H-E method in terms of vasospasm, edema in the tunica media, and folding of the lamina elastica interna.Results: The co-administration of melatonin and miRs-17/20 reduced the vasospasm and edema formation in the vessel wall. It has also been demonstrated that the application of miRs-17/20 after SAH alone reduces the development of edema in the vessel wall and folding of the internasal lamina elastica due to vasospasm.Conclusion: It has been shown that miRs-17/20 can reduce vasospasm in the vessel wall and prevent vessel damage by reducing edema.

Melatonin attenuates cardiopulmonary toxicity induced by benzo(a)pyrene in mice focusing on apoptosis and autophagy pathways.

Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon and a serious environmental pollutant. BaP is formed by the incomplete combustion of organic matter at high temperatures. In addition, tobacco smoke and many foods, especially charbroiled food and grilled meats, contain BaP and can cause it to enter human body. Melatonin, a pineal gland hormone, has antioxidant, anti-apoptosis, and autophagy regulatory properties. The possible protective impact of melatonin on cardiopulmonary toxicity induced by BaP was investigated by examining the antioxidant effects and the apoptosis and autophagy properties of melatonin. Thirty male mice were divided into 5 groups and treated for 28days as follows: (I) control (BaP and melatonin solvent), (II) BaP (75mg/kg, oral gavage), (III and IV) BaP (75mg/kg) + melatonin (10 and 20mg/kg, intraperitoneally), (V) melatonin (20mg/kg). The oxidative stress factors (MDA and GSH content) were assessed in the heart and lung tissues. The levels of apoptotic (Caspase-3 and the Bax/Bcl-2 ratio) and autophagic (the LC3 ӀӀ/Ӏ, Beclin-1, and Sirt1) proteins were examined by using western blot analysis. Following the administration of BaP, MDA, the Bax/Bcl-2 ratio, and the Caspase-3 proteins increased in the heart and lung tissues, while GSH, Sirt1, Beclin-1, and the LC3 II/I ratio diminished. The coadministration of melatonin along with BaP, MDA, and apoptotic proteins returned to the control values, while GSH and the autophagy proteins were enhanced in both the heart and lungs. Melatonin exhibited a protective effect against BaP-induced heart and lung injury through the suppression of oxidative stress and apoptosis and the induction of the Sirt1/autophagy pathway.

Toxic effects of excess exposure to boric acid on serum biochemical aspect, hematology and histological alterations and ameliorative potential role of melatonin in rats

The current work clarifies the negative effects of excess exposure to boric acid (H3BO3) as a boron-containing compound on rats and the possible ameliorative effect of melatonin (MEL). Forty rats were equally divided into 5 groups as follows: group 1 was treated as control while groups 2, 3, 4 and 5 were orally administered corn oil (0.5 ml), H3BO3 (1330 mg/kg BW), MEL (10 mg/kg BW) and H3BO3 + MEL for 28 consecutive days, respectively. At the end of the experiment, blood was sampled for biochemical and hematological analysis and tissues were collected for histopathological examination. The obtained results demonstrated that the exposure to H3BO3 induced hepatorenal dysfunctions, alterations in bone-related minerals and hormones levels, prostaglandin E2 as inflammatory mediator and hematological indices. H3BO3 induced histological alterations in the liver, kidneys, bone and skin. The co-administration of MEL with H3BO3 resulted in a significant improvement in most of the measured parameters and restoration of morpho-functional state of different organs compared to the H3BO3 group. In conclusion, the study clearly demonstrated that H3BO3- induced various adverse effects and that melatonin may be beneficial in a partial mitigating the H3BO3 and may represent a novel approach in the counteracting its toxicity.

Melatonin Alleviates Ovariectomy-Induced Cardiovascular Inflammation in Sedentary or Exercised Rats by Upregulating SIRT1.

We aimed to evaluate the impact of hormone replacement, melatonin, or exercise alone or their combination on oxidative damage and functional status of heart, brain, and aorta of ovariectomized (OVX) rats and to determine whether the signaling pathway is dependent on sirtuin-1 (SIRT1). Ovariectomized Sprague Dawley rats were orally given either a hormone replacement therapy (1mg/kg/day,17β estradiol; HRT) or melatonin (4mg/kg/day) or HRT + melatonin treatments or tap water, while each group was further divided into sedentary and exercise (30min/5days/week) groups. After the heart rate measurements and memory tests were performed, trunk blood was collected at the end of the 10th week to determine metabolic parameters in serum samples. Tissue samples of abdominal aorta, heart, and brain were taken for biochemical measurements and histopathological evaluation. Heart rates and memory performances of the OVX rats were not changed significantly by none of the applications. Melatonin treatment or its co-administration with HRT upregulated the expressions of IL-10 and SIRT1, reduced the expressions of IL-6 and TNF-α, and reduced DNA damage in the hearts and thoracic aortae of non-exercised rats. Co-administration of melatonin and HRT to exercised OVX rats reduced inflammatory response and upregulated SIRT1 expression in the aortic and cardiac tissues. The present study suggests that melatonin treatment, either alone or in combination with exercise and/or HRT, upregulates SIRT1 expression and alleviates oxidative injury and inflammation in the hearts and aortas of OVX rats. Melatonin should be considered in alleviating cardiovascular disease risk in postmenopausal women.

Administration of Melatonin in Diabetic Retinopathy Is Effective and Improves the Efficacy of Mesenchymal Stem Cell Treatment.

Stem cell transplantation is a promising therapeutic technique for the treatment of a variety of diseases; nevertheless, stem cell therapy may not always work as well as it could. The goal of this study was to test the hypothesis that employing a powerful antioxidant like melatonin improves stem cell transplantation success and potentiates stem cell function in the therapy of diabetic retinopathy. For this purpose, 50 adult male rats were divided into the following: control group: this group received 0.5 ml of 0.1 M of sodium citrate buffer (pH = 4.5) (intraperitoneal (I.P.)). The confirmed diabetic rats were divided into 4 groups: diabetic group: confirmed diabetic rats received no treatments with a regular follow of the blood glucose profile for 8 weeks; melatonin group: confirmed diabetic rats received melatonin (5 mg/kg/day); stem cell group: the confirmed diabetic rats were given intravitreal injection of stem cells (2 μl cell suspension of stem cells (3 × 104 cells/μl)); and melatonin+stem cell group: confirmed diabetic rats received melatonin (5 mg/kg/day), orally once daily for 8 weeks, and 2 μl cell suspension of stem cells (3 × 104 cells/μl) was carefully injected into the vitreous cavity. Our results showed that administration of melatonin and/or stem cell restored the retinal oxidative/antioxidant redox and reduced retinal inflammatory mediators. Coadministration of melatonin and stem cells enhanced the number of transplanted stem cells in the retinal tissue and significantly reduced retinal BDEF, VEGF, APOA1, and RBP4 levels as compared to melatonin and/or stem alone. We may conclude that rats treated with melatonin and stem cells had their retinal oxidative/antioxidant redox values restored to normal and their histological abnormalities reduced. These findings support the hypothesis that interactions with the BDEF, VEGF, APOA1, and RBP4 signaling pathways are responsible for these effects.

Influence of melatonin on systemic inflammatory status and bone histopathological modifications in female rats with surgically induced menopause

Background. Melatonin, N-acetyl-5-methoxy-tryptamine is the major secretion product of the pineal gland with important anti-inflammatory and antioxidant properties, also being an im-portant marker of bone remodelling associated with menopause. Objectives. The aim of our study was to evaluate the effect of the co-administration of melatonin and estrogen on systemic inflammatory status and bone histopathological modifications in surgically induced menopau-sal female rats. Materials and methods. The study was performed on a number of 40 female rats, Wistar breed, which underwent bilateral surgical ovariectomy. Within 14 days postoperative, hormone replacement therapy with estrogen or estrogen with melatonin was initiated, in differ-ent doses. The treatment was administered for 12 consecutive weeks. At the end of the treatment we measured the serum levels of IL-6 and TNF-α. The femoral bones were harvested after sacri-ficing the animals and the thickness of the cortical bones was measured and histologically ana-lysed. Results. Serum values of inflammatory markers were negatively correlated with melatonin ad-ministration, the differences being more important at higher doses of melatonin (for both IL-6 and TNF-α the difference between group E_2M with estrogen substitution and melatonin in double dose and control group W, without hormone replacement, was highly statistically signif-icant with p <0.0001). Bone diameters improved in the case of female rats that received hormone replacement with estrogen and higher dose of melatonin (p = 0.0004 between group E_2M, with hormone replacement and group W, control group). Conclusions. Melatonin improved inflam-matory status and bone histopathological changes in ovariectomized female rats. Keywords: melatonin, estrogen replacement therapy, inflammation, low bone density

Magnesium and Melatonin Co-Administration Attenuates Blood Glucose Levels in Streptozotocin-Induced Diabetic Rats

Diabetes mellitus (DM) is a serious metabolic disorder characterized by elevated blood glucose. The raised blood glucose level if not properly managed can results in damage and failure of several vital organs such as the eyes, kidneys, nerves, heart, and blood vessels. The aim of this study was to evaluate the effects of co-administration of melatonin and magnesium on blood glucose level of streptozotocin-induced Type 1 diabetic Wistar rats. To achieve this aim sixty-four Wistar rats were used in the study. Streptozotocin (STZ) was used to induce chemical type 1 diabetes mellitus (T1DM) after two weeks acclimatization period in fifty-eight Wistar rats. Fifty-three rats were diabetic and fourty-eight diabetic rats were randomly distributed in eight groups and six normal normoglycaemic rats were used as control. The animals were assigned into nine groups as follows, Normal control group (NC), Diabetic control (DC) group, Melatonin Low dose group of 10 mg/kgb (MLD), magnesium low dose group of 240 mg/kgbw (MgLD), melatonin and magnesium combined low dose group of 10mg/kgbw+240mg/kgbw (MMgLD), melatonin high dose group of 20mg/kgbw (MHD), magnesium high dose group of 480mg/kgbw (MgHD), melatonin and magnesium high dose combined group of 20mg/kgbw+480mg/kgbw (MMgHD) and insulin at 500mg/kgbw group (IN). Melatonin and insulin were administered through intraperitoneal injections (IP) while magnesium was by oral administration. The control groups were given placebo and all group treatment was for twenty-one days. Blood glucose was measured weekly in all groups by day 8, day 15 and day 22. At the end of the evaluation Day 22, the blood glucose levels showed a highly significant decrease (p˂0.05) in melatonin treatment group at low dose (MLD), melatonin and magnesium combined group at low doses (MMgLD), melatonin treatment group at high doses (MHD) and insulin treated group (IN) when compared with normoglycaemic group (NC) while groups treated with Magnesium at low doses (MgLD), magnesium treated group at high doses and melatonin and magnesium treatment group at high doses (MMgHD) showed no significant decrease (p˂0.05) in blood glucose levels as compared with diabetic control (DC). Melatonin and magnesium co-administration has hypoglycaemic effects on blood glucose levels in STZ-induced type 1 diabetic Wistar rats.

Effect of melatonin on paclitaxel-associated acute and chronic pain: a randomized, double-blind, placebo-controlled clinical trial

Background: Taxane-induced pain is a disabling condition. This trial was conducted to assess the effects of melatonin on preventing paclitaxel-associated acute and chronic pain or decreasing its severity in patients with breast cancer. Methods: This randomized, double-blind, placebo-controlled clinical trial was conducted on breast cancer women who received weekly paclitaxel (80 mg/m2) with or without trastuzumab after using doxorubicin + cyclophosphamide. The intervention group randomly received oral melatonin (10 mg/day) or placebo, which started from the first night of chemotherapy and continued through the planned 12 weeks of chemotherapy. The level of arthralgia-myalgia as acute pain was assessed every day in both groups using the Brief Pain Inventory (BPI). The Douleur Neuropathique 4 questionnaire (DN4) and National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 were used to measure chemotherapy-induced peripheral neuropathy as chronic pain. Results: Seventeen patients were enrolled in each group randomly. The incidence of neuropathy according to a DN4 score ≥ 4 was significantly lower in the melatonin group versus the placebo group at week 12 compared to baseline (5 vs 11, P-value= 0.039). In addition, the mean neuropathy severity was significantly lower in the melatonin group over time (β= -0.051, P-value= 0.01). However, there were no significant differences in the mean worst and least pain scores over the twelve cycles of treatment between arms (P-value= 0.633, 0.341 respectively). Conclusion: Co-administration of melatonin in women with breast cancer decreased the incidence of severe paclitaxel-associated neuropathy but melatonin was not effective against acute pain.

Coadministration of Melatonin and Insulin Improves Diabetes-Induced Impairment of Rat Kidney Function

Introduction: The present study was designed to evaluate the therapeutic efficacy of melatonin and insulin coadministration in diabetes-induced renal injury in rats. Research Design and Methods: Diabetes was achieved by giving streptozotocin (15 mg/kg) for 6 consecutive days. The diabetic condition was confirmed by assessing the blood glucose level; animals having blood glucose levels above 250 mg were considered as diabetic. Following the confirmation, animals were randomly divided into different experimental groups, viz group I served as the control (CON), group II diabetic (D), group III D+melatonin (MEL), group IV D+insulin (INS), group V D+MEL+INS, group VI D+glibenclamide (GB), group VII CON+MEL, group VIII CON+INS, and group IX CON+GB. Following the completion of the experimental period, animals were sacrificed, blood was collected via a retro-orbital puncture, and kidneys were harvested. Diabetic rats exhibited a significant increment in blood glucose and biochemical indexes of renal injury (tubular disruption, swollen glomeruli with loss of glomerular spaces, and distortion of the endothelial lining) including augmented levels of serum creatinine, urea, uric acid, Na+, and K+, and inhibition/suppression of the activity of glutathione (GSH) peroxidase, GSH reductase, glucose-6-phosphate dehydrogenase, and GSH-S-transferase in the renal cortex. Results: By examining thiobarbiturate reactive substances, reduced GSH, superoxide dismutase activity, and catalase activity in the renal cortex of control and diabetic rats, it was documented that treatment with melatonin or insulin alone or in combination showed a significant ad integrum recovery of GSH-dependent antioxidative enzymatic activities. Melatonin and insulin coadministration caused greater reductions in circulating tumor necrosis factor-α, tumor growth factor-β1, interleukin (IL)-1β, and IL-6 levels in diabetic rats, whereas IL-10 levels increased, as compared to each treatment alone. Diabetic rats showed a significant increase in the expression of both MT1 and MT2 melatonin receptor genes. Melatonin or insulin treatment alone or in combination resulted in significant restoration of the relative expression of both melatonin receptors in the renal cortex. Conclusion: The coadministration of exogenous melatonin and insulin abolished many of the deleterious effects of type 1 diabetes on rat renal function.

Melatonin as a Therapeutic Agent for the Inhibition of Hypoxia-Induced Tumor Progression: A Description of Possible Mechanisms Involved.

Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis.

Molecular Mechanism of Neuroprotective Effect of Melatonin on Morphine Addiction and Analgesic Tolerance: an Update.

Drug addiction is a global health problem and continues to place an enormous financial burden on society. This addiction is characterized by drug dependence sensitization and craving. Morphine has been widely used for pain relief, but chronic administration of morphine causes analgesic tolerance, hyperalgesia, and addiction, all of which limit its clinical usage. Alterations of multiple molecular pathways have been reported to be involved in the development of drug addiction, including mitochondrial dysfunction, excessive oxidative stress and nitric oxide stress, and increased levels of apoptosis, autophagy, and neuroinflammation. Preclinical and clinical studies have shown that the co-administration of melatonin with morphine leads to a reversal of these affected pathways. In addition, murine models have shown that melatonin improves morphine-induced analgesic tolerance and addictive behaviors, such as behavioral sensitization, reward effect, and physical dependence. In this review, we attempt to summarize the recent findings about the beneficial effect and molecular mechanism of melatonin on mitochondrial dysfunction, uncontrolled autophagy, and neuroinflammation in morphine addiction and morphine analgesic tolerance. We propose that melatonin might be a useful supplement in the treatment opiate abuse.

Melatonin increases the anticancer potential of doxorubicin in Caco-2 colorectal cancer cells.

Colorectal cancer (CC) is an important human malignancy with high cancer related death worldwide. The chemotherapy using doxorubicin hydrochloride is one of the most common cancer therapeutic methods. However, drug resistance lowers the treatment efficacy in CC patients. The combination therapies seem to be more promising by taking the advantage of synergistic effects. The present study aimed to evaluate a new strategy to enhance the anticancer activity of doxorubicin in Caco-2 CC cell line by co-administration of melatonin. The effects of doxorubicin, melatonin, and their combinations (Dox-Mel) were investigated on the proliferation and viability, morphological alterations, and tumor spheroid formation. Flow cytometry was employed to compare the apoptotic situation of the cells in study groups. Changes in metastatic potential of the cells were assessed by wound healing assay and trans-well migration assays. Moreover, expression of BAX, SMAC, BCL-2, SURVIVIN, MMP-2, and MMP-9 genes were evaluated by quantitative real time PCR and western blotting. Our study showed that doxorubicin, melatonin, and Dox-Mel significantly decreased the proliferation and viability, tumor spheroid formation, invasion, and migration. Furthermore, the changes were in a concentration and time dependent manner. There was an increase in apoptosis rate in the treatment groups. Expression of genes involved in apoptosis and cell motility were altered significantly. It was observed that anticancer activity of Dox-Mel combination was significantly more than doxorubicin and melatonin treatments alone. We showed an enhanced apoptotic and anticancer activity of doxorubicin and melatonin combination chemotherapy on CC cell line than doxorubicin or melatonin treatments alone. This combination could promote the treatment efficiency and alleviate the un-intended side effects by lowering the dose of doxorubicin prescription.

A Randomized, Controlled, Parallel-Group, Trial on the Effects of Melatonin on Fatigue Associated with Breast Cancer and Its Adjuvant Treatments.

Objective:Fatigue associated with malignant conditions and their treatments is a disabling condition. This trial assessed the anti-fatigue effects of melatonin coadministration during adjuvant treatment of patients with the breast cancer.Material and Methods:Patients with breast cancer were randomly assigned to receive melatonin or placebo during adjuvant chemotherapy and radiotherapy. Thirty-seven patients were randomly enrolled in each group. The mean ages of patients in the intervention and control groups were 50.47 ± 10.79 and 46.05 ± 10.55 years, respectively (P = .223). The intervention group received oral melatonin (18 mg/day) from 1 week before until 1 month after the adjuvant radiotherapy. The level of fatigue was assessed before and after intervention using Brief Fatigue Inventory (BFI) in both groups. To analyze data, the Student’s t-test and the Chi-square test were used at a significance level of P ≤ .05.Results:The BFI score was similar before the intervention in both groups, however, after the intervention, it was significantly lower in the melatonin group (P < .001). Moreover, the frequency of severe fatigue in the melatonin group was significantly lower than in the placebo group after intervention (42.1% vs 83.3%, P < .001).Conclusion:Coadministration of melatonin during adjuvant chemotherapy and radiotherapy of women with breast cancer decreased the levels of fatigue associated with the malignant condition and its treatments.

Melatonin and Magnesium Restores Neurohistopathological Changes in the Hippocampus of Streptozotocin-Induced Diabetic Rats

Diabetic encephalopathy and its associated end organ damage have become a major global epidemic in many patients with diabetes mellitus. These diseased conditions are complex and poorly understood, therefore the need to seek for alternative management measures to attenuate the complications associated with it. The aim of this study was to evaluate the effects of co-administration of melatonin and magnesium on the cytoarchitecture of the hippocampus of streptozotocin (STZ) induced diabetic rats. STZ was used to induce type 1 diabetes mellitus. Fifty four rats: Forty eight diabetic and six normoglycaemic rats distributed in nine groups as follow; normal control, diabetic control (DC), melatonin low dose (MLD, 10 mg/kg), magnesium low dose (MgLD, 240 mg/kg), melatonin and magnesium combined dose (MMgLD, 10 mg/kg+240 mg/kg, respectively), melatonin high dose (MHD, 20 mg/kg), magnesium high dose (MgHD, 480 mg/kg), melatonin and magnesium high dose (MMgHD, 20 mg/kg+480 mg/kg, respectively) and insulin (IN, 500 mg/kg). Melatonin and insulin were administered through intraperitoneal injections while magnesium was orally. The control groups were given placebo and all treatments were for twenty-one days. Results showed distortion of hippocampal CA1 area in the diabetic control, MgLD, MgHD, MMgHD and IN groups. MLD, MHD and MMgLD groups showed organized structures of hippocampus CA1 area with no cellular distortions, while there were less positive GFAP in the MLD, MHD and MMgLD groups. The DC, MgLD. MgHD, MMgHD and IN groups showed strong GFAP reactivity. In conclusion, MLD, MHD and MMgLD increased neuroprotection of hippocampal neurocytes

Melatonin alleviates morphine analgesic tolerance in mice by decreasing NLRP3 inflammasome activation

Morphine is frequently used for pain relief, but long-term morphine therapy in patients with chronic pain results in analgesic tolerance and hyperalgesia. There are no effective therapeutic treatments that limit these detrimental side effects. We found pretreatment with melatonin could decrease morphine-induced analgesic tolerance. There was a significant activation of the NLRP3 inflammasome in the prefrontal cortex and the peripheral blood of morphine-treated mice compared to control animals, which could be blocked by melatonin. The inflammasome activation induced by morphine was mediated by the microglia. SiRNA knockdown or pharmacological inhibition of the NLRP3 abolished the morphine-induced inflammasome activation. Co-administration of melatonin and low-dose morphine had better analgesia effects in the murine models of pain and led to a lower NLRP3 inflammasome activity in brain tissues. Mice deficient for Nlrp3 had a higher nociceptive threshold and were less sensitive to develop morphine-induced analgesic tolerance and acetic acid-induced pain relative to wild-type animals. Concordantly, we observed a significantly elevated level of serum IL-1β, which indicates an increase of NLRP3 inflammasome activity associated with the reduced level of serum melatonin, in heroin-addicted patients relative to healthy individuals. Our results provide a solid basis for conducting a clinical trial with the co-administration of melatonin and morphine for the relief of severe pain.