Melatonin treatment for prevention of oxidative stress: involving histopathological changes

This study was undertaken to test the effect of irradiation on the histopathology of the hypothalamus and cerebral cortex. In addition, the probable effects of radiotherapy on the activities of antioxidant enzymes and levels of nitric oxide (NO) in the plasma were investigated as well. The effects of melatonin treatment on radiotherapy-based central nervous system (CNS) damage were also studied. For this purpose, the rats were randomized into four groups. The first group was the control group (sham-exposed group), the second group received only melatonin, the third group was irradiated and the fourth group received both melatonin and irradiation. Plasma samples of rats were collected for measuring the activities of superoxide dismutase (SOD), catalase (CAT) and the levels of NO. 24 h after the interventions, tissue samples were obtained from the hypothalamus and the cerebral cortex for the light microscopic investigations. These tissues were mostly affected by radiation. The results indicated that the application of radiation significantly enhanced the levels of plasma SOD and NO. On the other hand, melatonin pretreatment prevented the decrease in plasma CAT activity induced by irradiation. It was found that the application of melatonin could significantly prevent the irradiation-induced damages. Light microscopic results revealed that the damage of the CNS by radiation was prevented by the application of melatonin.     

Antioxidative role of melatonin in organophosphate toxicity in rats

Previous studies revealed that oxidative stress could be an important component of the mechanism of organophosphate (OP) compound toxicity. The aim of the present study was to investigate both prophylactic and therapeutic effects of melatonin against fenthion-induced oxidative stress in rats. Therefore, we determined the changes in the levels of reduced glutathione (GSH) and malondialdehyde (MDA) in the whole blood, brain, pectoral muscle, liver, lung, heart, kidney, pancreas, and jejunum. Also, the changes in the levels of serum nitrite and nitrate, ascorbic acid, retinal, b-carotene, and ceruloplasmin were measured. In addition, activities of enzymatic antioxidants superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in erythrocyte of normal and experimental animals were measured. It was found that fenthion administration increased the levels of MDA in all tissues and decreased or increased the levels of GSH in some tissues. In comparison to nitrate, nitrite and ascorbic acid levels in the serum of experimental groups, there was no significant difference between groups. However, fenthion toxicity led to decrease in retinol and β-carotene levels; melatonin administration significantly prevented this decrease. Serum ceruloplasmin level was increased due to fenthion administration, but prophylactic and therapeutic melatonin administration inhibited the increase in ceruloplasmin level of serum. There was no significant change in SOD levels in melatonin-administered groups. Melatonin modulates the fenthion-induced changes in the activities of GPx and CAT. In conclusion, the results of the current study revealed that OP toxicity, induced by fenthion, activated oxidant systems in all antioxidant systems in some tissues. Melatonin administration led to a marked increase in antioxidant activity and inhibited lipid peroxidation in most of tissues.     

Antioxidant tolerance of kidney after irradiation

Different doses of irradiation were performed in which group 1 (non-irradiated), group 2 (8 Gy/single dose/whole body) and group 3 (15 Gy/single dose/whole body) were formed of guinea pigs. After 24 hr of radiation exposure the levels of lipid peroxidation product, malondialdehyde, (MDA), glutathione (GSH) and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured in the whole kidney. The MDA content increased in animals irradiated with 8 and 15 Gy. And group 3 showed an increase the level of MDA. GSH contents of kidney in group 2 and 3 increased. The activity of SOD decreased markedly in group 3 when compared with control group. The activity of GSH-Px decreased significantly in group 2 and group 3 in comparison to controls. It may be concluded that a high dose of ionizing irradiation cause excessive oxidative stress in kidney.     

Melatonin ameliorates ionizing radiation-induced oxidative organ damage in rats

This study was designed to study the effects of the potential radioprotective properties of pharmacological doses of melatonin against organ damage induced by whole-body irradiation (IR) in rats. A total of 32 male Sprague-Dawley rats were exposed to irradiation performed with a LINAC producing 6 MV photons at a focus 100 cm distant from the skin. Under ketamine anaesthesia, each rat received a single whole-body dose of 800 cGy. Immediately before and after IR, rats were treated with either saline or melatonin (20 mg/kg and 10 mg/kg, i.p.) and decapitated at 12-h after exposure to irradiation. Another group of rats was followed for 72-h after IR, where melatonin (10 mg/kg, i.p.) injections were repeated once daily. Tissue levels of malondialdehyde (MDA)--an index of lipid peroxidation--, glutathione (GSH)--a key to antioxidant--and myeloperoxidase (MPO) activity--an index of neutrophil infiltration--were estimated in liver, lung, colon and intestinal tissues. The results demonstrate that both 12-h and 72-h following IR, tissue levels of MDA were elevated (p<0.05-0.001), while GSH levels were reduced (p<0.05-0.001) in all organs. On the other hand, melatonin, reduced the levels of MDA and increased the GSH levels significantly, (p<0.05-0.001). MPO activity was increased significantly in the colonic tissue at the both 12-h and 72-h, and in the hepatic tissue at the 72-h following IR, which were reduced by melatonin (p<0.01-0.001). In the lung tissue enzyme activity was decreased at 72nd h of post-irradiation. In conclusion, the increase in MDA levels and MPO activity and the concomitant decrease in GSH levels demonstrate the role of oxidative mechanisms in irradiation-induced tissue damage, and melatonin, by its free radical scavenging and antioxidant properties, ameliorates irradiation-induced organ injury. Thus, supplementing cancer patients with adjuvant therapy of melatonin may have some benefit for successful radiotherapy.     

Effects of melatonin on oxidative-antioxidative status of tissues in streptozotocin-induced diabetic rats

In view of the antioxidant properties of melatonin, the effects of melatonin on the oxidative-antioxidative status of tissues affected by diabetes, e.g. liver, heart and kidneys, were investigated in streptozotocin (STZ)-induced diabetic rats in the present study. Concentrations of malondialdehyde (MDA) and reduced glutathione (GSH), and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the tissues were compared in three groups of 10 rats each (control non-diabetic rats (group I), untreated diabetic rats (group II) and diabetic rats treated with melatonin (group III)). In the study groups, diabetes developed 3 days after intraperitoneal (i.p.) administration of a single 60 mg kg(-1) dose of STZ. Thereafter, while the rats in group II received no treatment, the rats in group III began to receive a 10 mg kg(-1) i.p. dose of melatonin per day. After 6 weeks, the rats in groups II and III had significantly lower body weights and higher blood glucose levels than the rats in group I (p < 0.001 and p < 0.001, respectively). MDA levels in the liver, kidney and heart of group II rats were higher than that of the control group (p < 0.01, p < 0.05, p < 0.01, respectively) and diabetic rats treated with melatonin (p < 0.05). The GSH, GSH-Px and SOD levels increased in diabetic rats. Treatment with melatonin changed them to near control values. Our results confirm that diabetes increases oxidative stress in many organs such as liver, kidney and heart and indicate the role of melatonin in combating the oxidative stress via its free radical-scavenging and antioxidant properties.     

Melatonin prevents oxidative kidney damage in a rat model of thermal injury

Animal models of thermal trauma implicate oxygen radicals as causative agents in local wound response and distant organ injury following burn. This study was designed to determine the effect of melatonin treatment on levels of glutathione (GSH), malondialdehyde (MDA), protein oxidation (PO) and myeloperoxidase (MPO) activity in the kidney tissues of rats with thermal injury. Under ether anaesthesia, shaved dorsum of the rats was exposed to 90 degrees C bath for 10 s to induce burn injury. Rats were decapitated either 3 h or 24 h after burn injury. Melatonin was administered i.p. immediately after burn injury. In the 24-h burn group melatonin injections were repeated for two more occasions. In the sham group the same protocol was applied except that the dorsum was dipped in a 25 degrees C water bath for 10 s. Severe skin scald injury (30% of total body surface area) caused a significant decrease in GSH level, and significant increases in MDA and PO levels, and MPO activity at post-burn 3 and 24 hours. Treatment of rats with melatonin (10 mg/kg) significantly elevated the reduced GSH levels while it decreased MDA and PO levels as well as MPO activity.     

Protective effect of melatonin against oxidative stress on adhesion formation in the rat cecum and uterine horn model

This experimental study was designed to evaluate the degree of adhesion formation and peritoneal tissue levels of malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NO) and the effect of melatonin on these metabolites in a postoperative intraperitoneal adhesion formation model in rats. Thirty adult female Wistar albino rats were subjected to standardized lesions by cecal and uterine horn abrasion and were randomly divided into three groups. Control rats were treated with 5% ethanol. Melatonin treated rats received 4 mg/kg melatonin before closure and for 10 consecutive days intraperitoneally after surgery. Rats in the sham operation group underwent a surgical procedure similar to the other groups however the peritoneal abrasion was not performed. On postoperative day 10 relaparatomy was performed. After the assessment of the adhesions, the rats in each group were sacrificed and peritoneal tissues were harvested to determine the tissue levels of MDA, GSH and NO activity. Adhesion formation scores in the melatonin group were significantly lower than that of control and sham group (p<0.01 and p<0.02, respectively). Tissue levels of MDA and NO were significantly lower in the melatonin treated rats when compared with control and sham groups. The levels of GSH in the melatonin treated rats were significantly higher than those of control and sham groups (p<0.01). The results demonstrate that in this experimental model, intraperitoneal administration of melatonin decreases the extent of peritoneal adhesions and causes a decrease in MDA and NO and an increase in GSH levels.     

Melatonin treatment protects against sepsis-induced functional and biochemical changes in rat ileum and urinary bladder

Sepsis is commonly associated with enhanced generation of reactive oxygen metabolites, which lead to multiple organ dysfunction. The aim of this study was to examine the role of melatonin, a potent antioxidant, in protecting the intestinal and bladder tissues against damage in a rat model of sepsis. Sepsis was induced by cecal ligation and perforation (CLP) in Wistar Albino rats. Sham operated (control) and CLP group received saline or melatonin (10 mg/kg, ip) 30 minutes prior to and 6 hours after the operation. Sixteen hours after the surgery, rats were decapitated and the intestinal and urinary bladder tissues were used for contractility studies, or stored for the measurement of malondialdehyde (MDA) content -an index of lipid peroxidation-, glutathione (GSH) levels -a key antioxidant- and myeloperoxidase (MPO) activity- an index of neutrophil infiltration-. Ileal and bladder MDA levels in the CLP group were significantly increased (p < 0.001) with concomitant decreases in GSH levels (p < 0.01 - p < 0.001) when compared to the control group. Similarly, MPO activity was significantly increased (p < 0.001) in both ileum and bladder tissues. On the other hand, melatonin treatment significantly reversed (p < 0.001) the elevations in MDA and MPO levels, while reduced GSH levels were increased back to the control levels (p < 0.01 - p < 0.001). In the CLP group, the contractility of the ileal and bladder tissues decreased significantly compared with controls. Melatonin treatment of the CLP group restored these responses. In this study, CLP induced dysfunction of the ileal and bladder tissue of rats was reversed by melatonin treatment. Moreover, melatonin, as an antioxidant, abolished the elevation in lipid peroxidation products and myeloperoxidase activity, and reduction in the endogenous antioxidant glutathione and thus protected the tissues against sepsis-induced oxidative damage.     

Melatonin Modulates Hippocampus NMDA Receptors, Blood and Brain Oxidative Stress Levels in Ovariectomized Rats

We investigated the effects of melatonin administration on ovariectomy-induced oxidative toxicity and N-methyl-d-aspartate receptor (NMDAR) subunits in the blood of rats. Thirty-two rats were studied in three groups. The first and second groups were control and ovariectomized rats. Melatonin was daily administrated to the ovariectomized rats in the third group for 30 days. Blood, brain cortical and hippocampal samples were taken from the three groups after 30 days. Brain cortical, erythrocyte and plasma lipid peroxidation (LP) levels were higher in the ovariectomized group than in controls, although the LP level was decreased in the ovariectomized group with melatonin treatment. Brain cortical and plasma concentrations of vitamins A, C and E as well as the NMDAR 2B subunit were lower in the ovariectomized group than in controls, although, except for plasma vitamin C, they were increased by the treatment. Brain cortical and erythrocyte reduced glutathione (GSH) levels were lower in the ovariectomized group than in controls, although erythrocyte GSH levels were higher in the melatonin group than in the ovariectomized group. Brain cortical and erythrocyte glutathione peroxidase activity and NMDAR 2A subunit concentrations were not found to be different in all groups statistically. Oxidative stress has been proposed to explain the biological side effect of experimental menopause. Melatonin prevents experimental menopause–induced oxidative stress to strengthen antioxidant vitamin and NMDAR 2A subunit concentrations in ovariectomized rats.     

Pinealectomy increases oxidant damage in kidney and testis caused by hyperthyroidism in rats

Thyroid hormones regulate energy metabolism and act on mitochondria which are an important source of free radicals in the cell. The pineal gland activates antioxidant systems via melatonin secretion and thus has a protective function in body tissues. The present study was conducted to determine the oxidative damage caused by hyperthyroidism in kidney and testis tissues of pinealectomized rats. Experimental animals were allocated to three groups: 1, control group; 2, sham pinealectomy-hyperthyroidic group; and 3, pinealectomy-hyperthyroidic group. Hyperthyroidism was induced by A 3-week intraperitoneal administration of thyroxin after sham pinealectomy or pinealectomy. Malondialdehyde (MDA) and glutathione (GSH) levels were determined in kidney and testis tissues. MDA levels of the kidney and testis tissue in the pinealectomy and hyperthyroidic groups were significantly higher than those in the sham pinealectomy-hyperthyroidic group and the control group (p < 0.001). GSH levels of both kidney and testis tissues were significantly higher in the sham-pinealectomy-hyperthyroidic group when compared to the other two groups (p < 0.001). This increase in GSH levels was more evident in the pinealectomy-hyperthyroidic group than in the control group (p < 0.001). The results of our study demonstrate that MDA and GSH levels in kidney and testis tissues increased due to hyperthyroidism and that pinealectomy made the increase in MDA levels more apparent, while decreasing GSH levels.     

Effects of Bacillus thuringiensis toxin on hepatic lipid peroxidation and free-radical scavengers in rats given alpha-tocopherol or acetylsalicylate

The effect of Dipel (D), a Bacillus thuringiensis-based bioinsecticide, on hepatic antioxidant enzyme activities and lipid peroxidation in rat liver was investigated. Administration of D in a dose of 1 mg/100 g body mass for 4 successive days increased the activities of glutathione peroxidase (GPx), glutathione reductase (GR) and the level of malondialdehyde (MDA) in rat hepatocytes. The activity of superoxide dismutase (SOD) and glutathione (GSH) level were decreased. Administration of D in rats pretreated with alpha-tocopherol (alphaT) or acetylsalicylic acid (ASA) decreased the activities of GPx, GR and MDA levels, while the GSH level was increased compared with rats treated with D alone. The SOD activity was increased in rats pretreated with alphaT before D, but decreased on pretreatment with ASA, compared with rats treated with D alone. The results indicated that D induced oxidative stress in rat liver that has been protected by prior administration of alphaT or ASA.     

The Roles of Melatonin and Vitamin E Plus Selenium in Prevention of Oxidative Stress Induced by Naloxone-Precipitated Withdrawal in Heroin-Addicted Rats

The therapeutic effects of melatonin or vitamin E plus Se (vE + Se) on the restrain of the heroin withdrawal-induced oxidative stress were studied. For this, rats were divided into ten groups. The rats were injected by fixed or variable doses of heroin for 16 consecutive days, and naloxone was given 1 h after the last heroin injection. One hour after naloxone administration, some groups were treated with melatonin or vE + Se. After 1 h this, blood samples were taken, and the levels of malondialdehyde (MDA) and reduced glutathione (GSH) in whole blood, ascorbic acid, α-tocopherol, retinol, β-carotene, nitrite, nitrate, and ceruloplasmin levels in the serum were measured. Our findings showed that, naloxone administration precipitated the heroin withdrawal. This also increased the level of MDA and decreased the levels of GSH in blood. Melatonin or vE + Se administration prevented the rise in MDA levels and increased the GSH levels. On the other hand, there were some significant differences between α-tocopherol, retinol, β-carotene, nitrite, nitrate, and ceruloplasmin levels of experimental groups. Results of present study showed that heroin withdrawal increased the lipid peroxidation and depressed endogenous antioxidative systems. Additionally, melatonin or vE + Se administrations prevented lipid peroxidation and augmented endogenous antioxidant defense systems.     

Neuroprotective effect of melatonin on radiation-induced oxidative stress and apoptosis in the brainstem of rats

This study aimed to determine the effects of melatonin on irradiation-induced apoptosis and oxidative stress in the brainstem region of Wistar rats. Therefore, the animals underwent whole-brain X-radiation with a single dose of 25 Gy in the presence or absence of melatonin pretreatment at a concentration of 100 mg/kg BW. The rats were allocated into four groups (10 rats in each group): namely, vehicle control (VC), 100 mg/kg of melatonin alone (MLT), irradiation-only (RAD), and irradiation plus 100 mg/kg of melatonin (RAM). An hour before irradiation, the animals received intraperitoneal (IP) melatonin and then were killed after 6 hr, followed by measurement of nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and total antioxidant capacity (TAC) in the brainstem region. Furthermore, the western blot analysis technique was performed to assess the caspase-3 expression level. Results showed significantly higher MDA and NO levels in the brainstem tissues for the RAD group when compared with the VC group (p < .001). Moreover, the irradiated rats exhibited a significant decrease in the levels of CAT, SOD, GPx, and TAC (p < .01, p < .001, p < .001, and p < .001, respectively) in comparison to the VC group. The results of apoptosis assessment revealed that the expression level of caspase-3 significantly rose in the RAD group in comparison with the VC group (p < .001). Pretreatment with melatonin ameliorated the radiation-induced adverse effects by decreasing the MDA and NO levels (p < .001) and increasing the antioxidant enzyme activities (p < .001). Consequently, the caspase-3 protein expression level in the RAM group showed a significant reduction in comparison with the RAD group (p < .001). In conclusion, melatonin approximately showed a capacity for neuroprotective activity in managing irradiation-induced oxidative stress and apoptosis in the brainstem of rats; however, the use of melatonin as a neuroprotective agent in humans requires further study, particularly clinical trials.     

The effect of melatonin against oxidative damage during total-body irradiation in rats

Melatonin has been reported to participate in the regulation of a number of important physiological and pathological processes. Melatonin, which is a powerful endogenous antioxidant, may play a role in the prevention of oxidative damage. The aim of this study was to investigate the effect of pretreatment with melatonin (5 mg kg(-1) and 10 mg kg(-1)) on gamma-radiation-induced oxidative damage in plasma and erythrocytes after total-body irradiation with a single dose of 5 Gy. Total-body irradiation resulted in a significant increase in plasma and erythrocyte MDA levels. Melatonin alone increased the levels of SOD and GSH-Px. Erythrocyte and plasma MDA levels in irradiated rats that were pretreated with melatonin (5 or 10 mg kg(-1)) were significantly lower than those in rats that were not pretreated. There was no significant difference between the effects of 5 and 10 mg kg(-1) on plasma MDA activities and CAT activities. However, erythrocyte MDA levels showed a dose-dependent decrease, while GSH-Px activities increased with dose. Our study suggests that melatonin administered prior to irradiation may protect against the damage produced by radiation by the up-regulation of antioxidant enzymes and by scavenging free radicals generated by ionizing radiation.     

Dantrolene protects erythrocytes against oxidative stress during whole-body irradiation in rats

In our study, we examined the radioprotective effects of dantrolene against gamma irradiation-induced damage of blood cells after total body irradiation of rats. Rats were divided into three groups of eight rats each. The first group was the control group receiving no dantrolene or irradiation, the second group received total body irradiation (RT) with 5 Gy of gamma irradiation only, and the third group received dantrolene at a dose of 5 mg x kg(-1) plus RT. Dantrolene was given intraperitoneally 30 min before RT. All groups were sacrificed 2 h after RT, and blood samples were taken. Leukocyte, and thrombocyte counts and hemoglobin levels were measured. Furthermore, malondialdehyde (MDA) levels in plasma and erythrocytes and superoxide dismutase (SOD) and glutathione peroxidase activities (GSH-Px) in erythrocytes were determined. It was found that pretreatment with dantrolene at a dose of 5 mg x kg(-1) significantly reduced the MDA levels and increased the antioxidant SOD and GSH-Px activities, and prevented the decrease in leukocyte and thrombocyte counts. We conclude that dantrolene has clear antioxidant properties when given prior to radiation exposure and the protective effect of dantrolene against damage inflicted by radiation, depends, at least in part, on the decrease in lipid peroxidation and increase in the activity of antioxidant enzymes SOD and GSH-Px.     

Amelioration of methotrexate-induced enteritis by melatonin in rats

The anti-tumour drug methotrexate (MTX) induces intestinal mucosa injury resulting in malabsorption and diarrhoea. The purpose of this study was to investigate whether exogenous melatonin could protect the gut from MTX-induced damage in rats. A single dose of MTX (20 mg kg(-1), i.p.) was followed by i.p. saline or melatonin injections (10 mg kg(-1), MTX + Mel) for the next 5 days. On the fifth day, intestinal transit was assessed using charcoal propagation. Rats were decapitated and small intestinal segments were fixed for light (LM) and scanning electron microscope (SEM) examinations. Other intestinal segments were stored to measure glutathione (GSH) and malondialdehyde (MDA) levels, myeloperoxidase (MPO) and ATPase activity. MTX led to loss of more than 10% of the initial body weight (p < 0.01). Conversely, weight loss was markedly less in the melatonin-treated MTX group (p < 0.05). Bowel motility was increased in MTX-treated rats, while the transit index in the MTX-Mel group was not different from the control group. MTX caused decreases in GSH levels and ATPase activity, with increases in MDA levels and MPO activity. These changes were reversed in MTX-Mel-treated rats (p < 0.05-p < 0.001). LM and SEM in the MTX group revealed desquamation of surface epithelium and glandular degeneration, while the epithelium was slightly damaged in the MTX-Mel group. In conclusion, the present study demonstrates that melatonin is capable of reversing MTX-induced intestinal dysfunctions, indicating that it may be beneficial in ameliorating the symptoms of chemotherapy-induced enteritis.     

Effects of melatonin in reducing the toxic effects of doxorubicin

Anthracycline antibiotics, such as doxorubicin and daunorubicin, constitute a group of wide spectrum therapeutic agents. Application of these drugs in chemotherapy is limited because of their toxic effects. Melatonin, the main secretory product of pineal gland, was recently found as a free radical scavenger and antioxidant.We decided to evaluate the tissue protective effect of melatonin against toxic effects of doxorubicin in six groups of rats. Rats were given doxorubicin (Dx) (45 mg/kg dose), melatonin (MEL) (10 mg/kg), first doxorubicin and then melatonin (DM), first melatonin and then doxorubicin (MD).The degree of kidney, lung, liver and brain cells' alterations were examined biochemically.In doxorubicin-treated group, malondialdehyde (MDA) levels of kidney, lung, liver and brain tissues were significantly increased but glutathione (GSH) levels were decreased compared to control rats. In the group in which first doxorubicin and then melatonin were given, MDA levels were significantly decreased compared to the doxorubicin-treated group.In doxorubicin-treated group, serum levels of creatinine, uric acid, blood urea nitrogen (BUN), Gamma-glutamyl transpeptidase (GGT) and Lactic acid dehydrogenase (LDH) were significantly increased while serum albumin and total protein levels were significantly decreased compared to control rats.Melatonin decreased the intensity of the changes produced by the administration of doxorubicin alone. Melatonin was quite efficient in reducing the formation of lipid peroxidation, restoring the tissue GSH contents and alterations of serum levels.     

Oral administration of melatonin modulates the expression of tumor necrosis factor-α (TNF-α) gene in irradiated rat cervical spinal cord

AimWe aimed to determine the changes in TNF-α expression and Malondialdehyde (MDA) level in a short time after irradiation. Furthermore, we evaluated the effect of melatonin on the modulation of TNF-α gene expression.BackgroundThe radio-sensitivity of the cervical spinal cord limits the dose of radiation which can be delivered to tumors in the neck region. There is increasing evidence that TNF-α has a role in the development of the acute phase of spinal cord injury.Materials/MethodsFour groups of rats were investigated. Group 1 (vehicle treatment) served as the control. Group 2 (radiation) was treated with the vehicle, and 30 min later, the rats were exposed to radiation. Group 3 (radiation + melatonin) was given an oral administration of melatonin (100 mg/kg body weight) and 30 min later exposed to radiation in the same manner as in group 2. Group 4 (melatonin-only) was also given an oral administration of melatonin (100 mg/kg body weight). 5 mg/kg of melatonin was administered daily to rats in groups 3 and 4, and the vehicle was administered daily to rats in groups 1 and 2.ResultsThree weeks after irradiation, TNF-α gene up-regulated almost 5 fold in the irradiated group compared to the normal group. TNF-α gene expression in the melatonin pretreatment group, compared to the radiation group, was significantly down-regulated 3 weeks after irradiation (p < 0.05). MDA levels increased after irradiation and then significantly decreased under melatonin treatment.ConclusionWe suggest that inhibition of TNF-α expression by oral administration of melatonin may be a therapeutic option for preventing radiation-induced spinal cord injury.     

Melatonin suppresses iron-induced neurodegeneration in rat brain

The antioxidative action of melatonin on iron-induced neurodegeneration in the nigrostriatal dopaminergic system was evaluated in vivo. Intranigral infusion of iron chronically degenerated the dopaminergic transmission of the nigrostriatal system. An increase in lipid peroxidation in the infused substantia nigra and reductions in dopamine levels and dopaminergic terminals in the ipsilateral striatum were observed 7 d after iron infusion. Whereas local infusion of melatonin (60 microg/microl, 1 microl) alone did not alter dopaminergic transmission, coinfusion of melatonin with iron suppressed iron-induced oxidative damages. Systemic infusion of melatonin via osmotic pumps had no effect on iron-induced neurodegeneration. However, repetitive intraperitoneal injections of melatonin (10 mg/kg) prevented iron-induced oxidative injuries. The ratio of glutathione (GSH)/oxidized glutathione (GSSG) was moderately increased in the lesioned substantia nigra of the melatonin-treated rats compared to that of the lesioned group in control rats. The antioxidative effect of melatonin was verified in cortical homogenates. Melatonin dose-dependently suppressed autoxidation and iron-induced lipid peroxidation. Melatonin was as effective as GSH and was less effective than Trolox (a water-soluble analogue of vitamin E) in inhibiting iron-elevated lipid peroxidation of brain homogenates. Our data suggest that melatonin is capable of at least partially preventing the iron-induced neurodegeneration in the nigrostriatal dopaminergic system.     

Two-phase response of rat pineal melatonin to lethal whole-body irradiation with gamma rays.

Male Wistar rats adapted to artificial light:dark (LD) regimen 12:12 h were whole-body irradiated with a single dose of 9.6 Gy of gamma rays and sham/irradiated in the night in darkness. The rats were examined 60 min, 1, 3 and 5 days after exposure between 22:00 and 01:30 h in the darkness. The results obtained indicate a two-phase reaction of pineal melatonin after the lethal irradiation of rats: the decline of melatonin concentration early after the exposure (at 60 min) with unchanged serotonin N-acetyltransferase (NAT) activity followed by an increase of melatonin synthesis, accompanied by an increase of pineal and serum melatonin on day 5 after the exposure. NAT activity was increased on day 3 after the exposure. Serum corticosterone concentrations in irradiated rats were increased 60 min and 3 days after exposure. With respect to the antioxidant, immunomodulating and stress-diminishing properties of melatonin, we consider the increase in melatonin synthesis during later periods after irradiation as part of adaptation of the organism to overcome radiation stress.