Search

Coronavirus disease 2019 (COVID-19) is a life-threatening infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 pandemic causing morbidities and even deaths worldwide revealed that there is urgent need to find pharmacological agents or vaccines. Although there are a lot of agents under investigation, there is no approved agent for the prevention or treatment of the COVID-19 yet. Treatment of patients remains mainly supportive as well as compassionate use of the agents under investigation. It is well established that excessive inflammatory and immune response and oxidative injury play a critical role in the pathogenesis of COVID-19. In this review, we aimed to update knowledge about pathogenesis, clinical features, and pharmacological treatment of COVID-19 and review the potential beneficial effects of ancient antioxidant, anti-inflammatory, and immunomodulatory molecule melatonin for prevention and treatment of COVID-19., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Background: The aging process is not univocal, both body and brain age. Neurological disorders are a major cause of disability and death worldwide. According to the Global Burden of Disease Study 2015, neurological diseases are the second most common cause of death and 16.8% of total deaths are caused by neurological diseases worldwide. Neurological disease deaths have risen 36% worldwide in 25 years. Melatonin is a neuroregulator hormone that has free radical scavenger, strong antioxidant, anti-inflammatory, and immunosuppressive actions. These major properties of melatonin can play an important role in the pathophysiological mechanisms of neurological diseases. In addition, melatonin is necessary for circadian rhythm. Studies have shown that melatonin levels are low in people with neurological diseases. Both preventive and therapeutic effects of melatonin are known for many diseases, including neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headache, etc.). Based on all these reasons, clinical trials of melatonin were performed and successful results were declared., Conclusions: In this review, biological and chemical knowledge of melatonin, its experimental effects, and the clinical impact on patients with neurological disorders were described. According to all of the beneficial results obtained from experimental and clinical trials, melatonin may have a prophylactic and therapeutic effect on neurological diseases. Strong collaboration between neurologists and health service policy makers is needed to encourage use of melatonin in the patients suffering from neurological diseases. Melatonin may be the solution we have been looking for., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

We evaluated the effects of melatonin on acetylsalicylic acid (ASA) induced gastroduodenal and jejunal mucosal injury. We used 40 postpubertal rats divided randomly into five groups of eight animals. The control group consisted of untreated animals. The Mel group was injected intraperitoneally (i.p.) with 5 mg/kg melatonin. The ASA group was injected i.p. with 200 mg/kg ASA. The ASA + Mel group was injected i.p. with 5 mg/kg melatonin 45 min after administering 200 mg/kg ASA i.p. The Mel + ASA group was injected i.p. with 5 mg/kg melatonin 45 min before administering 200 mg/kg ASA i.p. We found no statistically significant differences in mean histopathological scores in the ASA + Mel group compared to the ASA group. ASA caused shortened villi and loss of the apical villus in the duodenum. The histopathological score was increased and villus height was decreased in the ASA group compared to untreated controls. Treatment with melatonin attenuated the histological damage. In the ASA group, occasional areas showed erosion of villi in the jejunum; however, differences in mean histopathological score in ASA group compared to the other groups were not statistically significant. Malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) activities were measured in stomach, duodenal and jejunum tissue. We found increased MDA activity in both stomach and duodenal tissues in the ASA group compared to the control group (p < 0.05). We found no statistically significant changes in MDA levels in jejunal tissue in the ASA group compared to the control group. We found no change in SOD activity in either stomach or duodenal tissues in the ASA group compared to the control group. We observed decreased SOD activity in jejunal tissue in the ASA group compared to the control group (p < 0.05). We detected no change in GSH activity in stomach, duodenal or jejunal tissues in the ASA group compared to the control group. The stomach damage was less in melatonin treated groups, but the lesions were not completely eliminated. The jejunum in the ASA group retained a nearly normal appearance. We found that melatonin exhibited some healing effects on ASA induced duodenal mucosal injury.

Objectives: The aim of this study was to examine the effects of melatonin on ionized radiation-induced salivary gland damage using an experimental model., Materials and Methods: Thirty-two rats were randomized into four groups: (i) the control group (C, n = 8) that received intraperitoneal (i.p.) 0.9% NaCl; (ii) the melatonin group (M, n = 8) that received i.p. 5 mg/kg melatonin; (iii) the radiotherapy group (RT, n = 8) that underwent irradiation; (iv) the melatonin plus radiotherapy group (M+RT, n = 8) that received i.p. 5 mg/kg of melatonin, followed by irradiation 30 min later; and (v) the radiotherapy plus melatonin group (RT+M, n = 8) that received irradiation followed by i.p. 5 mg/kg of melatonin 30 min later. The medications and irradiation were administered for 5 days and the salivary glands of the rats were excised 10 days later; the histopathological changes in the salivary glands were assessed and biochemical analyses were conducted (tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI))., Results: Regardless of whether melatonin was administered before or after radiotherapy, melatonin decreased the radiation-induced parotid and submandibular histological damage. In addition, regardless of whether administration occurred before or after radiotherapy, melatonin decreased oxidative stress markers, such as MDA, TOS, and OSI. On the contrary, levels of antioxidative markers, such as CAT and GPx, were increased by melatonin., Conclusions: Melatonin may have a significant protective effect on salivary gland damage secondary to ionizing radiation., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives/hypothesis: To examine the effects of N-acetyl-5-methoxytryptamine (melatonin) on radiation-induced inner ear damage., Study Design: An experimental animal model., Methods: Forty rats were randomized into five groups, as follows: 1) melatonin and then radiotherapy group (n = 8), which received intraperitoneal (i.p.) melatonin (5 mg/kg) followed by irradiation 30 minutes later; 2) radiotherapy and then melatonin group (n = 8), which received irradiation with i.p. melatonin (5 mg/kg) 30 minutes later; 3) melatonin group (n = 8), which received i.p. melatonin (5 mg/kg); 4) radiotherapy group (n = 8), which underwent only irradiation; 5) and the control group (n = 8), which received i.p. 0.9% NaCl. The medications and irradiation were administered for 5 days. All rats underwent the distortion product otoacoustic emission (DPOAE) test before and 10 days after the experiment. The middle ears of the rats were excised, and assessment of tissue alterations in the organs of Corti, spiral ganglions, and stria vascularis were compared among the groups., Results: In the radiotherapy group, the DPOAE amplitudes at frequencies of 4000 to 6000 Hz were significantly decreased when compared with the controls. The DPOAE amplitudes both in the melatonin and then radiotherapy group and the radiotherapy and then melatonin group exhibited better values than they did in the radiotherapy group. Histopathological evidence of damage to the organs of Corti, spiral ganglions, and stria vascularis damage was markedly reduced in both these two groups when compared to the radiotherapy group., Conclusion: These results indicate that melatonin may have significant ameliorative effects on cochlear damage secondary to ionizing radiation., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the prototype of a group of highly toxic environmental chemicals. Although there are some suggestions regarding TCDD-induced cardio-toxicity, the exact mechanisms underlying this process have not been fully discovered. One mechanism related to this toxicity is believed to be the generation of reactive oxygen species. Melatonin is known to be a strong antioxidant and has a free radical scavenging ability. Therefore, the aim of this study was to investigate the TCDD-induced cardio-toxicity and the protective effects of melatonin in rats. Rats were randomly divided into 4 equal groups (n=7 for each group). Group 1 was control; group 2 was TCDD group (2µg/kg/week, p.o); group 3 was melatonin group (5mg/kg/day, i.p.) and group 4 was TCDD and melatonin treatment group. All agents were continued to be administered until the 45th day. Body/heart weights, mean oxygen saturation (PO2%), hemodynamic [mean blood pressure (MBP) and heart rate (HR) from the cannulated-carotid artery] and electrocardiographic evaluations (arrhythmias and duration of PR, QRS and QT intervals), biochemical and histopathological analysis were carried out. TCDD exposure caused significant body and heart weight loss, impairment of PO2%, and decrease of MBP and HR levels. Also, major ECG changes and prolongation of PR, QRS and QT durations were observed in TCDD-exposed rats. In biochemical analysis, TCDD significantly induced lipid peroxidation and reduced antioxidant activities. Moreover, our histopathological observations were in accordance with the biochemical results. According to the results, melatonin treatment significantly protected the subjects from TCDD-induced cardio-toxicity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate the acute effect of high-dose acetylsalicylic acid (ASA) on kidney and testis, and the potential protective and therapeutic effects of melatonin on ASA-related pathology. A total of 40 rats were randomly divided into the following 5 groups (n = 8): group 1: control, not given any drug; group 2: only 200 mg/kg ASA was given; group 3: 5 mg/kg melatonin was given 45 min before administering 200 mg/kg ASA; group 4: 5 mg/kg melatonin was given 45 min after administering 200 mg/kg ASA; and group 5: only 5 mg/kg melatonin was given. The histopathological changes and the biochemical findings; such as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), reduced glutathione (GSH), and blood urea nitrogen (BUN) as well as serum creatinine (Cr) levels were evaluated. ASA significantly increased MDA levels in both kidney and testis, whereas it significantly decreased the values of SOD, CAT, GPX, and GSH in kidney and CAT levels in testis. Melatonin significantly decreased MDA levels in kidney and ameliorated it in testis, whereas it caused elevation in the levels of antioxidants. BUN and Cr levels were higher after ASA, whereas these levels were diminished after melatonin administration. The improvement obtained by melatonin on ASA-induced histological alterations was more prominent when it was used after ASA in kidney and before ASA in testis. In this study, we demonstrated the beneficial effect of melatonin on high-dose ASA-related pathology of kidney and testis for the first time.

Objective: The incidence of urinary bladder disturbances and renal structural changes and functional decline are found to increase with age., Methods: We investigated the effect of melatonin treatment in addition to estrogen replacement therapy in pinealectomized (Px) and ovariectomized (Ovx) rats. 56 female Wistar rats were divided into seven groups, each containing eight animals: Sham, (Ovx), (Px), Px+Ovx, Px+Ovx receiving estrogen (Px+Ovx+E), Px+Ovx receiving melatonin (Px+Ovx+M) and Px+Ovx estrogen and melatonin supplemented (Px+Ovx+EM) group (EM group). We evaluated reduced glutathione (GSH) levels and malondialdehyde (MDA) levels. The mean collagen fiber (CF)/smooth muscle (SM) ratio in the bladder wall and structure of the kidney were examined histolologically. We also recorded response of the bladder contractility to acetylcholine (Ach)., Results: Px and Ovx groups showed statistically significant reductions of antioxidant defenses, impaired Ach-evoked contraction, histological changes compared with the control group. Also, these changes were prominent in Px+Ovx group compared with all other groups. Both estrogen and melatonin reversed these changes however best restoration was observed in the EM group., Conclusions: Px performed in addition to Ovx led to a distinct increase in oxidative damage in bladder and renal tissue and deteriorate of the detrussor function. Either estradiol or melatonin replacement alone or in combination prevents significant alterations of tissue histology and bladder contractility following Ovx and Px. Thus, combination treatment appears to be the best method to restore both contractility and histomorphology of bladder and kidney tissues after Ovx and Px (Tab. 3, Fig. 4, Ref. 44).

Objectives: The aim of this study was to investigate the possible protective effects of melatonin and β-d-glucan against ischemia-reperfusion (IR) injury in rats., Material and Methods: Forty rats were randomly divided into 5 groups, each consisting of 8 animals, as follows. Sham group [S], IR group [C], IR + β-Glucan group [β], IR + melatonin group [MLT], IR + melatonin + β-Glucan group [MLT + β]. The rats in the C, β, MLT and MLT + β groups were subjected to IR for 60 min each. Melatonin (10 mg∙kg⁻¹) was intraperitoneally injected for a single dose 30 min before IR. β-Glucan (50 mg∙kg⁻¹∙day⁻¹) was orally administered for 10 days to rats. All of the rats were killed on day 11, and histological changes in the liver and tissue levels of oxidants and antioxidants were evaluated., Results: Malondialdehyde [MDA] level were significantly higher in the C group compared to the S group (p = 0.007). MDA level were significantly higher in the β group compared to the MLT and MLT + β groups (p =0.007). Tissue antioxidant markers (superoxide dismut ase [SOD], glutathione-peroxidase [GPx], and catalase [CAT]) were significantly lower in the C group than the S group (p < 0.05). SOD levels were simply not significant in the β group compared to the MLT and MLT + β groups. CAT and GPx activities were significantly higher in the β group compared to the MLT and MLT + β groups (p = 0.004).The histological damage ameliorated in β, MLT and MLT + β groups compared to C group.

Inflammatory bowel disease has been linked to elevated T cells. Excessive production of reactive oxygen species and apoptosis are known to be accompanied by intestinal inflammation. This study was designed to investigate the effects of melatonin (MEL) and erythropoietin (EPO), which is a known anti-inflammatory and antiapoptotic agent, in dinitrobenzene sulfonic acid (DNBS)-induced colitis in pinealectomized (Px) rats. In microscopically results, epithelial and goblet cell loss, absence of crypts, and increased colonic caspase-3 activity were observed in the DNBS group. Also, in flow cytometric analysis, the percentage of CD4+ T cells was highest in the DNBS group. Treatment with MEL or EPO had a curative effect on DNBS-induced colitis. The MEL + EPO groups showed significantly greater improvement when compared with the other treatment groups. Our results indicate that the combination of EPO and MEL may exert more beneficial effects than either agent used alone., (© 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Although melatonin has been implicated in several neurophysiological systems, data on the relationship of melatonin with psychosis such as schizophrenia are limited and contradictory. Chronic effects of melatonin on sensorimotor gating deficits have also not been investigated yet. We investigated the neurobehavioral effects of chronic administration of melatonin in pinealectomized (Px) and ovariectomized (Ovx) rats. Px or Ovx or both operations were carried out together to the rats. The control group of rats was sham operated. A sham ovariectomy was carried out to Px rats, and vice versa. Fifth month later, melatonin (5mg/kg) or vehicle was injected to rats for 28 days. Then, prepulse inhibition (PPI) of acoustic startle reflex, startle amplitude and startle reflex latency was measured. Locomotor activity, accelerod performance measurements, novel object recognition and passive avoidance tests were also evaluated. Px and Px+Ovx rats had impaired PPI compared to control rats. Melatonin reversed the impairments of PPI induced by Px or Px+Ovx. While melatonin treatment had no effect on locomotor activity of control rats, it significantly increased the locomotor activity of Px and Px+Ovx rats. Melatonin treatment (5mg/kg/day, 28 days) reversed the locomotor hyperactivity caused by Ovx. Accelerod performance, passive avoidance, and object recognition responses of Px, Ovx or Px+Ovx rats were not different from the control group. Our results indicate that chronic melatonin deficiency by reason of Px results in impairment of PPI reflex and replacement of melatonin exerts beneficial effects on the impaired PPI reflex in Px and Ovx rats. Thus, melatonin may be useful in the treatment of some disorders characterized by sensorimotor gating deficits such as schizophrenia., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: It is generally agreed that physiological levels of melatonin, a hormone secreted by the pineal gland, are important in protecting against oxidative stress-induced tissue damage., Aim: We investigated the effects that pinealectomy and the administration of exogenous melatonin have on the brains, testes, duodena and stomachs of rats., Materials and Methods: Pinealectomized (Px) and sham-operated (non-Px) rats were used. We evaluated structural changes, and catalase (CAT), reduced glutathione (GSH), super oxide dismutase (SOD) and malondialdehyde (MDA) levels. The rats were divided into the following five groups (eight rats in each group): sham (non-Px), Px+ vehicle, Px+ melatonin (10 mg/kg given daily intraperitoneally for a week), melatonin and ethyl alcohol., Results: The antioxidant levels in the tissue of Px rats were significantly lower than in those of the sham group. Administering melatonin significantly increased antioxidant levels (p < 0.05). The Px rats also showed a significant increase in MDA levels when compared to the sham group, and administering melatonin to the Px rats significantly reduced their MDA levels (p < 0.05). The severity of caspase-3 staining was lower in the Px+ melatonin group than in the Px+vehicle group., Conclusions: These findings suggest that significantly more oxidative and structural changes occur in rats' brains, spinal cords and testes after pinealectomy, but that this can be diminished by melatonin treatment. However, Px does not have important effects on the duodenum and stomach.

In the present study, we investigated the in vivo effects of melatonin on SAH-induced cerebral vasospasm and oxidative stress, resulting from SAH in an experimental rat model. Twenty-eight rats (225-250 g) were divided into four groups equally: group 1; control, group 2; SAH, group 3; SAH plus placebo, and group 4; SAH plus melatonin. We used double haemorrhage method for SAH groups. Beginning 6 h after SAH, 20 mg/kg melatonin or equal volume of 0.9% saline was administered intraperitoneally twice daily for 5 days to groups 3 and 4, respectively. Melatonin or 0.9% saline injections were continued up to fifth day after SAH and rats were sacrificed at the end of this period. Brain sections at the level of the pons were examined by light microscopy. The lumen diameter and the vessel wall thickness of basilar artery were measured using a micrometer. The serum levels of cerebral vasodilator nitric oxide (NO), the brain levels of an intrinsic antioxidant superoxide dismutase (SOD) and a NO regulator arginase activities were measured. The brain levels of inducible nitric oxide (iNOS) and nitrotyrosine, a nitrosative stress parameter immunohistochemiacally determined. In conclusion, melatonin administration ameliorated cerebral vasospasm by increasing serum NO level and decreasing the brain the levels of arginase and oxidative stress. It is therefore possible that increased brain arginase activity after SAH may also have a significant role in the pathogenesis of vasospasm by limiting the availability of arginine for NO production.

Oxidative stress may have a role in liver damage after acute renal injury due to various reasons such as ischemia reperfusion (IR). Diabetes mellitus (DM) is an important disease for kidneys and may cause nephropathy as a long term complication. The aim of this study was to investigate protective effect of melatonin, a potent antioxidant, against distant organ injury on liver induced by renal IR in rats with or without DM. The rats were divided into six groups: control (n=7), DM (n=5), IR (n=7), DM+IR (n=7), melatonin+IR (Mel+IR) (melatonin, 4 mg/ kg during 15 days) (n=7), and Mel+DM+IR groups (n=7). Diabetes developed 3 days after single i.p. dose of 45 mg/kg streptozotocin. After 15 day, the left renal artery was occluded for 30 min followed 24 h of reperfusion in IR performed groups. DM did not alter oxidative parameters alone in liver tissue. The levels of malondialdehyde, protein carbonyl and nitric oxide with activities of xanthine oxidase and myeloperoxidase were increased in liver tissues of diabetic and non-diabetic IR groups. Nitric oxide level in DM was higher than control. The activities of catalase and superoxide dismutase were increased in IR groups in comparison with control and DM. ALT and AST levels were higher in IR and DM+IR groups than control and DM. Melatonin treatment reversed all these oxidant and antioxidant parameters to control values as well as serum liver enzymes. We concluded that renal IR may affect distant organs such as liver and oxidative stress may play role on this injury, but DM has not an effect on kidney induced distant organ injury via oxidant stress. Also, it was concluded that melatonin treatment may prevent liver oxidant stress induced by distant injury of kidney IR.

Background: An animal model of myocardial ischemia-reperfusion (MI/R) was used to test the hypothesis that free radicals released with MI/R have hazardous effects on liver through remote organ injury., Material/methods: Twenty-one rats were divided into three groups: sham-treated, MI/R, and MI/R+melatonin. To produce MI/R, a branch of the left coronary artery was occluded for 30 min followed by two hours of reperfusion. Melatonin or vehicle was given 10 min before ischemia. At the end of the study, liver tissue was obtained for biochemical determination. The false discovery rate (FDR) is explained and was used for multiple comparisons of the groups' means., Results: Compared with the sham group, MI/R significantly decreased glutathione (GSH) content and increased levels of nitric oxide (NO) and malondialdehyde (MDA). Melatonin administration significantly increased GSH levels and decreased the levels of NO and MDA compared with the MI/R group., Conclusions: Melatonin could prevent liver damage due to its strong antioxidant and free radical scavenger effects. Therefore, melatonin may have beneficial effects on remote organ injury such as MI/R-induced liver disorders.

Aim: The purpose of the current study was to investigate the effects melatonin on renal function., Methods: The histological appearance of the kidney and malondialdehyde, nitric oxide, glutathione and superoxide dismutase contents were determined. Serum creatinine and blood urea nitrogen levels were also assayed. Rats were divided as: Sham, pinealectomized (Px) and pinealectomized and treated with melatonin., Results: In Px group, malondialdehyde and nitric oxide levels were elevated when compared with the sham group. The Px group exhibited reduced superoxide dismutase activity and glutathione content. All of these harmful changes were restored by melatonin. Melatonin also ameliorated serum creatinine and blood urea nitrogen levels related to renal injury. The score for glomerular, tubular and interstitial changes was significantly higher in the Px group. Melatonin supplementation significantly reduced these parameters., Conclusions: This protective effect may be associated with both melatonin's lipophilic and hydrophilic effects, thus providing on-site protection against free radical mediated damage.

Aims: The purpose of this study was to investigate the effects of chronic administration of melatonin on renal ischemia/reperfusion (IR) injury in streptozotocin (STZ)-induced diabetic rats., Methodology: Male Sprague-Dawley rats were divided into six groups: control (C), diabetes mellitus (DM), control+IR (C+IR), DM+IR, Melatonin+IR (Mel+IR), DM+Mel+IR. Diabetic and non-diabetic rats were given melatonin 4 mg/kg/day, i.p., for 15 days. The left renal artery and vein of rats were occluded for 30 min at the 18th day, followed by 24 h of reperfusion., Results: In comparison with control group, the levels of malondialdehyde (MDA), protein carbonyl (PC) and and nitric oxide (NO) were determined to be higher in the renal homogenates of DM, DM+IR and C+IR groups. MDA and NO levels were found to be similar in the DM+melatonin+IR and control groups. The most significant histological damage was found in the DM+IR group and this damage was significantly reduced by melatonin., Conclusion: Chronic melatonin treatment reduces renal injury by reducing lipid oxidation and NO production in STZ-induced diabetic rats exposed to IR.

Recently we have reported a significant reduction in the thickness of epidermis and epidermis + dermis in the back, abdominal and thoracic skin of the long-term pinealectomized rats and the potent therapeutic effect of melatonin on the pinealectomy-induced morphometric changes. The present study was aimed to determine the fine structure of the abdominal and thoracic skin in pinealectomized rats and the effect of melatonin on skin ultrastructure. Rats were pinealectomized or sham operated (control) for 6 months. Half of the pinealectomized rats were treated with 4 mg/kg melatonin during the last month of the experiment. Pinealectomy resulted in prominent ultrastructural changes in the skin. Epidermal atrophy, disorganization and cytological atypia were obvious. Tonofilament distribution was not uniform, and intercellular space was narrow. Nuclear irregularity and heterochromatin condensation were detected. Many mitochondria were irregular and edematous with increased translucence of the matrix, either partial or total destruction of crests and frequently the presence of vacuoles, myelin figures and dense bodies. Microprojections of basal cells into the dermis were observed. The dermis was thin, and collagenous fibers were loosely arranged. The epidermis in melatonin administered pinealectomized rats was obviously thicker than that of pinealectomized rats. The cells of each layers had characteristic morphological and ultrastructural features. Nuclear irregularity and heterochromatin condensation were not seen. Mitochondria were generally normal in ultrastructural appearance but rarely vacuoles and myelin figures were observed. The dermis was thick, and collagenous fibers were closely packaged. This paper provides an additional ultrastructural evidence that the damage to mitochondria is the major contributory factor to skin aging and that melatonin has potent therapeutic effects in reducing age-related changes via protecting fine structure of the skin.

The aim of this study was to define the characteristics of heart rates and myocardial changes in rats exposed to carbon monoxide (CO), and the effects of reoxygenation, atenolol (a beta-blocker) and melatonin after sublethal CO intoxication. Widespread use of beta-blockers in cardiology practice and growing literature on the positive effect of melatonin in ischaemia reperfusion lead us to question their effects in case of CO intoxication. Rats were exposed to CO. After sublethal intoxication the rats were reoxygenated with ambient air. Subsequently blood values, electrocardiographic recordings and pathological changes were examined for each groups. Five rats died after CO intoxication in the control group: no myocardial changes were seen in light microscopy. However, myocardium of seven reoxygenated rats presented contraction bands. Seven reoxygenated rats pretreated with atenolol had a higher number of contraction bands of myocardial cells. Seven reoxygenated rats pretreated with melatonin had more contraction bands than reoxygenated rats, and heart rate recordings of these animals revealed a profund and sustained bradycardia. Thus, melatonin and atenolol appear to have some adverse effects in CO intoxication on the myocardial cells.

Inadequate blood perfusion and ischemia-reperfusion (I/R) injury in the surgical skin flap are believed to be the major factors that cause harmful changes within the tissue and vasculature, resulting in flap necrosis. Reactive oxygen radical species (ROS), in part, are believed to play an important role in this injury. Melatonin, in many physiological conditions, has been shown to have direct and indirect antioxidative effects and free-radical-scavenging properties. Therefore, it may have a beneficial effect on I/R-induced flap injury. In this study, the possible protective effects of melatonin were investigated in I/R injury of rat epigastric (axial pattern) flaps. Ischemia was achieved for 12 h by occlusion of inferior epigastric artery. Melatonin or vehicle was administered 1 h before flap elevation and was continued for 6 days after ischemia. I/R injury elevated malondialdehyde (MDA), an end product of lipid peroxidation, and nitric oxide (NO) levels while the glutathione (GSH) content was reduced. Myeloperoxidase (MPO) activity, which is known to be related to tissue neutrophil accumulation, was found to be statistically higher in the I/R group when compared with the sham group. Administration of melatonin significantly decreased MDA, NO and MPO levels and elevated the GSH content. Moreover, melatonin reduced the flap necrosis area, which was determined using a planimetric method. In conclusion, melatonin, a potent scavenger of free radicals, plays a major role in preventing the inferior epigastric arterial I/R-induced flap necrosis, based on planimetric flap survival and biochemical results. The beneficial effects of melatonin in I/R injury implies the involvement of free radicals in flap damage.

Purpose: To investigate whether a protein kinase C (PKC) inhibitor and melatonin prevent proliferative vitreoretinopathy (PVR)., Methods: Twenty pigmented rabbits were used in this study. All rabbits except controls received an intravitreal injection of 0.15 ml (75,000 units) of platelet-rich plasma into their left eye. The animals were divided into four groups: group I was treated with intravitreal injection of 0.1 ml (100 micromol/ml) of PKC inhibitor (chelerythrine chloride), group II received 1 ml (4 mg/kg) of intraperitoneal melatonin for 3 days, group III received nothing (blank group), and group IV (control group) received only 0.5 ml of 1% ethanol intraperitoneally for 3 days. Proliferative changes were graded in a masked fashion by indirect ophthalmoscopy for a 15-day follow-up period. The malondialdehyde (MDA), reduced glutathione (GSH) and total nitrite levels were measured in the vitreous humor., Results: The grades of PVR were A and B in group I and II, treated with PKC inhibitor and melatonin, respectively. The PVR grade in the blank group was C-D. The mean MDA level in group I (4.2 +/- 0.9 micromol/l) was significantly lower than in the blank group (6.0 +/- 1.0 micromol/l; p < 0.05). The mean GSH level in group I (66.3 +/- 8.8 micromol/l) was not significantly different from that in the blank group (p > 0.05). The MDA and GSH levels in group II were 3.2 +/- 0.7 and 70.1 +/- 13.3 micromol/l, respectively. Both these levels were significantly different from those of the blank group (p < 0.05). The NO levels in both treatment groups were significantly lower than in the blank group (p < 0.001)., Conclusion: These findings suggest an inhibitory effect of PKC inhibitor and melatonin on PVR. The inhibition of PVR development was associated with lower MDA and NO levels with higher GSH levels in the treatment groups., (2006 S. Karger AG, Basel)

The goal of this study was to investigate the effect of melatonin on basic cerebral metabolites in pinealectomized (Px) rat brains. Twenty-one rats were randomly divided into three groups with seven rats per group. The study groups included sham-operated rats, Px rats and Px rats treated with melatonin. Melatonin administration began at 60 days following pinealectomy and continued for 21 days. At the end of the study, in vivo single voxel magnetic resonance spectroscopy was performed on whole brains to determine choline (Cho), creatine and N-acetyl aspartate (NAA) concentrations. Px rats had significantly lower NAA levels (P<0.05), and significantly higher Cho levels (P<0.05) when compared with sham-operated rats. Administration of melatonin had normalized NAA and Cho levels in Px rats. We propose that pinealectomy causes significant changes in cerebral metabolites which are compatible with neural loss. Melatonin administration prevents the disruptive effects of pinealectomy on brain tissue.

It is generally agreed that one of the major contributors to skin aging is reactive oxygen species. As organisms reach advanced age, free radical generation increases and the activity of tissue antioxidant enzyme system decreases. Melatonin is an antioxidant and free radical scavenger. The present study was first aimed to determine the morphometric and biochemical changes caused by long-term pinealectomy in order to investigate the role of melatonin as skin architecture. Secondly, the effect of exogenous melatonin administration on these changes was determined. Rats were pinealectomized or sham operated (control) for 6 months. Half of the pinealectomized rats were treated with 4 mg/kg melatonin during the last month of the experiment. Pinealectomy resulted in important morphometric and biochemical changes in the back, abdominal and thoracic skin. The thickness of epidermis and dermis and the number of dermal papillae and hair follicles were reduced. Melatonin administration to pinealectomized rats significantly improved these alterations in all body areas (P < 0.005). On the contrary, in pinealectomized rats the levels of antioxidant enzymes, catalase and glutathione peroxidase were decreased. Melatonin restored the levels of these enzymes. The pinealectomy-induced increases in lipid peroxidation in the abdominal and thoracic skin were significantly reduced by melatonin treatment (P < 0.005 and 0.01 respectively). These results suggest that melatonin is highly efficient anti-aging factor and, as melatonin levels decrease with age, melatonin treatment may reduce age-related skin changes.

Experimental studies indicate that ischemia/reperfusion (I/R) causes remote organ injury although the molecular mechanism has not been clearly defined. In this report, the role of oxidative injury on testicular damage following myocardial I/R injury and the effects of antioxidant agents, melatonin and caffeic acid phenethyl ester (CAPE), on testicular injury were investigated. As far as we know, this is the first report demonstrating that myocardial I/R induces damage to the testes. Thirty-two male Wistar rats were randomly divided into four groups: sham operation (SO), I/R + vehicle, I/R + melatonin, and I/R + caffeic acid phenethyl ester. To produce cardiac damage, the left main coronary artery was occluded for 30 min, followed by 120 min reperfusion, in anesthetized rats. Serum nitric oxide (NO) and malondialdehyde (MDA) levels and morphological changes were examined. I/R was accompanied by a significant increase in serum MDA and NO levels, whereas, melatonin and CAPE administration significantly reduced these values. Melatonin was more efficient in reducing MDA levels than CAPE (P < 0.05). I/R induced myocardial damage, manifested as the histopathological evidence of intracellular vacuolization, interstitial edema, neutrophil infiltration and coagulative necrosis. I/R + vehicle group showed many histological alterations such as focal tubular atrophy, and degeneration and disorganization of the seminiferous epithelium in testes. The number of atrophic tubules and degenerating cells was significantly higher in I/R + vehicle group than that of SO group. Melatonin and CAPE significantly reduced the number of degenerating cells; additionally, melatonin reduced the number of atrophic tubules (P < 0.05). Our results indicate that myocardial I/R induces severe testicular damage and antioxidant agents, especially melatonin, have protective effects on testicular injury after myocardial I/R. Our data emphasize that oxygen-based reactants may play a central role in remote organ injury.

Free radicals, calcium overloading and loss of membrane phospholipids play an important role in the development of ischemia/reperfusion (I/R) injury. Melatonin is a well-known antioxidant and free radical scavenger. Melatonin may also reduce the intracellular calcium overloading and inhibit lipid peroxidation. This study was designed to investigate the effects of melatonin on the I/R-induced cardiac infarct size in an in vivo rat model. We also investigated glutathione (GSH) levels, an antioxidant the levels of which are influenced by oxidative stress, and malondialdehyde (MDA) levels, which is an index of lipid peroxidation. To produce cardiac damage, the left main coronary artery was occluded for 30 min, followed by 120 min reperfusion, in anesthetized rats. Melatonin (10 mg/kg) or vehicle was given 10 min before ischemia via the jugular vein. Infarct size, expressed as the percentage of the risk zone, was found significantly greater in I/R group than in the melatonin-treated I/R group. MDA levels were significantly higher, but GSH levels were lower in the I/R group than in the control group. Melatonin significantly reduced the MDA values and increased the GSH levels. These results suggest that oxidative stress contributes to myocardial I/R injury and melatonin administration exerts a mitigating effect on infarct size. Furthermore, the results indicated that melatonin improves the antioxidant capacity of the heart and attenuates the degree of lipid peroxidation after I/R.

The effects of pinealectomy and administration of melatonin, the major secretory product of the pineal gland, which is a direct free radical scavenger and an indirect antioxidant, were studied in rat hearts on the basis of cardiac morphology and biochemical findings. Three groups of Wistar rats were used: one group was the sham-operated control, one group consisted of pinealectomized rats and one group consisted of pinealectomized rats that were treated with melatonin. Serum cholesterol, tissue levels of malondialdehyde (MDA) and reduced glutathione (GSH), and heart weight were determined. Histochemical staining with the Van Gieson, PAS/Alcian blue at pH 2.5 and Masson's trichrome methods were performed in addition to hematoxylin-eosin staining. Levels of serum cholesterol and tissue MDA, and heart weight were increased in pinealectomized rats whereas GSH levels did not change. Melatonin administration reversed these effects. Microscopically, myocardial fibrosis and myxomatous degeneration of cardiac valves were detected in all pinealectomized rats. It can be concluded that pinealectomy of rats causes morphological changes in rat hearts, and short-term application of melatonin does not reverse these changes.

Random pattern skin flaps are still widely used in plastic surgery. However, necrosis in the distal portion resulting from ischemia is a serious problem, increasing the cost of treatment and hospitalization. Free oxygen radicals and increased neutrophil accumulation play an important role in tissue injury and may lead to partial or complete flap necrosis. To enhance skin flap viability, a variety of pharmacological agents have been intensively investigated. The aim of this study is to test the effects of melatonin, the chief secretory product of the pineal gland and a highly effective antioxidant, on random pattern skin flap survival in rats. Herein, to investigate the physiological and pharmacological role of melatonin on dorsal skin flap survival. Pharmacological (0.4, 4 and 40 mg/kg) levels of melatonin were given intraperitoneally (i.p.). For this, pinealectomized (Px) and sham operated (non-Px) rats were used. The effects of melatonin on levels of malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH) and the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were measured in the skin flap. The ratio of skin flap necrosis was compared among the experimental groups by using planimetry. MDA and NO levels were found to be higher in Px than non-Px rats; while GSH levels and GSH-Px, and SOD activities were reduced. Melatonin administration to Px rats reduced MDA and NO levels and increased GSH, GSH-Px, SOD levels. Melatonin also reduced the ratio of flap necrosis determined by using planimetry and supported through the photography. In conclusion, these results show that both physiological and pharmacological concentrations of melatonin improve skin flap viability.

Previous observations demonstrated that physiological levels of melatonin, the pineal secretory product, are important in protecting against oxidative stress-induced tissue damage. We investigated the effects of pinealectomy and administration of exogenous melatonin on liver tissue in rats. Pinealectomized (Px) and sham-operated (non-Px) rats were used. We evaluated structural changes, reduced glutathione (GSH) levels and malondialdehyde (MDA) levels. Rats were divided into three groups (10 rats in each group): control (non-Px), Px+vehicle and Px+melatonin (4 mg/kg given daily intraperitoneally for 10 days). Liver GSH levels were significantly lower in Px rats than in the control group. Melatonin administration significantly increased GSH levels (p < 0.05). Px caused a significant increase in MDA levels as compared with the control group and melatonin administration to Px rats significantly reduced MDA levels in the liver (p < 0.05). Sinusoidal dilatation to a varying degree developed in all Px rats. Severity of mononuclear cell infiltration and sinusoidal congestion were lower in Px+melatonin group than in the Px group. These findings suggest that a significant increase in oxidative and structural changes occur in rat livers after pinealectomy, which can be diminished by melatonin treatment.

Doxorubicin (Dox) is a widely used antineoplastic drug. Oxygen radical-induced injury of membrane lipids is considered to be the most important factor responsible for the development of Dox-induced cardiotoxicity. The pineal secretory product, melatonin, is known to be a potent free radical scavenger and its pharmacological concentrations have been shown to reduce Dox-induced cardiac damage. However, the physiological role of melatonin in the prevention of this damage is unknown. We investigated physiological and pharmacological effects of melatonin on Dox-induced changes in the levels of malondialdehyde (MDA), a lipid peroxidation product, and morphological changes in heart. Rats were pinealectomized (Px) or sham-operated (control) 2 months before the studies. Melatonin was administered [4 mg/kg, intraperitoneally (i.p.)] 1 hr before or 24 hr after the administration of a single dose of Dox (20 mg/kg, i.p.) and continued for 2 days. The levels of MDA Dox was found to be significantly higher in the Px rats (55.9 +/- 0.6 nmol/g tissue) than intact control animals (42.6 +/- 0.4). Dox administration to Px and non-Px rats significantly increased the MDA levels. Pre- and post-treatment with melatonin in both Px and intact rats significantly reduced MDA levels. Morphological changes parallelled the MDA alterations. These findings strongly suggest that both physiological and pharmacological concentrations of melatonin are important in protecting the heart from Dox-induced damage in rats. It would seem valuable to test melatonin in clinical trials for prevention of possible heart damage associated with Dox.

It is well established that some agents such as aminoglycosides generate free oxygen radicals, leading to an increased oxireductase production, which in turn increases tissue toxicity. The aim of this study is to test whether melatonin, the chief secretory product of the pineal gland and a highly effective antioxidant and free radical scavenger, reduces the nephrotoxicity caused by amikacin (AK). Herein, we investigated the physiologic and pharmacological role of melatonin in influencing AK-induced nephrotoxicity. For this, pinealectomized (Px) and sham operated (non-Px) rats were used. Both AK and melatonin were administered to all groups. We investigated the effects of melatonin on AK-induced changes in levels of malondialdehyde (MDA), a lipid peroxidation product, glutathione (GSH), an antioxidant whose levels are influenced by oxidative stress, and blood urea nitrogen (BUN) and serum creatine (Cr) levels. Morphologic changes in the kidney were also examined by using light microscopy. MDA levels were found to be higher in Px than in non-Px AK-treated animals. Melatonin administration to Px rats reduced MDA levels. In relative to non-Px rats, Px animals treated with AK had significantly lower GSH concentrations while melatonin administration elevated GSH levels in the kidney; however, this stimulatory effect of melatonin was not observed in non-Px AK-treated rats. Treatment with AK alone resulted in significantly higher plasma Cr and BUN levels. Repeated administration of melatonin prevented the AK-induced elevation of plasma Cr and BUN levels. Morphologic damage to renal tubules as a result of AK was more severe in the renal cortex than in the medulla. The damage to the kidney induced by AK was reversed by melatonin in the Px rats. In conclusion, these results show that physiologic melatonin concentrations are important in reducing AK-induced renal damage, while pharmacologic concentrations of melatonin did not add to the beneficial effect.

Reactive oxygen species have been implicated in the pathophysiology of renal ischemia reperfusion (I/R) injury. The pineal secretory product melatonin is known to be a potent free radical scavenger and antioxidant. This study was designed to investigate the effects of physiological and pharmacological concentrations of melatonin on I/R injury. Rats were pinealectomized (Px) or sham-operated (control) 2 months before the I/R studies. There were eight groups of eight rats each. After a right nephrectomy to produce damage, left renal vessels were occluded for 60 min, followed by 24 h reperfusion, in rats. Malondialdehyde (MDA) levels resulting from I/R were significantly higher in the pinealectomized rats than in the control group. Melatonin administration (4 mg kg(-1) i.p. either before ischemia or reperfusion) to Px and sham-operated rats significantly reduced the MDA values and returned them to the control values. Morphological changes in the groups were similar to the MDA levels. Serum levels of blood urea nitrogen and creatine were unchanged. These results suggest that physiological and pharmacological melatonin concentrations are important for the reduction of I/R-induced damage. We also demonstrated that melatonin, even when administrated just before reperfusion, had a protective effect on I/R injury. It would seem valuable to test melatonin in clinical trials for the prevention of possible I/R injury.

Cisplatin [cis-diaminedichloroplatinum(II), CDDP] is a widely used antineoplastic drug. However, it has major side-effects such as acute tubular necrosis (ATN). There are a number of studies concerning the role of reactive oxygen radical species in the pathophysiology of CDDP-dependent ATN. Several antioxidant agents have been reported to prevent this side-effect but there is no study regarding the protective action of either physiological or pharmacological concentrations of melatonin. Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger and indirect antioxidant. We investigated the effects of melatonin on CDDP-induced changes of renal malondialdehyde (MDA), a lipid peroxidation product, and blood urea nitrogen (BUN) and serum creatine (Cr). The morphological changes in kidney were also examined using light microscopy. The rats were divided into two groups: pinealectomized (Px) and sham-operated (non-Px). Both CDDP and melatonin were administered to all groups. MDA levels were found to be higher in Px than non-Px animals. CDDP administration to Px or non-Px rats increased renal MDA levels and melatonin administration either before or after CDDP injection caused significant decreases in MDA in kidney compared with those in rats treated with CDDP alone. Serum levels of BUN and Cr did not change as a result of any treatment. Morphological tubule damage because of CDDP was more severe in the renal cortex than in the medulla. The damage to the kidney induced by CDDP was reversed by melatonin. The results show that pharmacological and physiological concentrations of melatonin reduce CDDP-induced renal injury.