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The purpose of this report is to emphasize the potential utility for the use of melatonin in the treatment of individuals who are infected with the Ebola virus. The pathological changes associated with an Ebola infection include, most notably, endothelial disruption, disseminated intravascular coagulation and multiple organ hemorrhage. Melatonin has been shown to target these alterations. Numerous similarities between Ebola virus infection and septic shock have been recognized for more than a decade. Moreover, melatonin has been successfully employed for the treatment of sepsis in many experimental and clinical studies. Based on these factors, as the number of treatments currently available is limited and the useable products are not abundant, the use of melatonin for the treatment of Ebola virus infection is encouraged. Additionally, melatonin has a high safety profile, is readily available and can be orally self-administered; thus, the use of melatonin is compatible with the large scale of this serious outbreak., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The presence of melatonin in plants is universal. Evidence has confirmed that a major portion of the melatonin is synthesized by plants themselves even though a homologue of the classic arylalkylamine N-acetyltransferase (AANAT) has not been identified as yet in plants. Thus, the serotonin N-acetylating enzyme in plants may differ greatly from the animal AANAT with regard to sequence and structure. This would imply multiple evolutionary origins of enzymes with these catalytic properties. A primary function of melatonin in plants is to serve as the first line of defence against internal and environmental oxidative stressors. The much higher melatonin levels in plants compared with those found in animals are thought to be a compensatory response by plants which lack means of mobility, unlike animals, as a means of coping with harsh environments. Importantly, remarkably high melatonin concentrations have been measured in popular beverages (coffee, tea, wine, and beer) and crops (corn, rice, wheat, barley, and oats). Billions of people worldwide consume these products daily. The beneficial effects of melatonin on human health derived from the consumption of these products must be considered. Evidence also indicates that melatonin has an ability to increase the production of crops. The mechanisms may involve the roles of melatonin in preservation of chlorophyll, promotion of photosynthesis, and stimulation of root development. Transgenic plants with enhanced melatonin content could probably lead to breakthroughs to increase crop production in agriculture and to improve the general health of humans.

Introduction: We designed the present study to evaluate the efficacy of melatonin (M) on the severity of necrotizing enterocolitis (NEC) in a neonatal rat model., Materials and Methods: Immediately after birth, pups were weighed and randomized into 3 groups: NEC, NEC + M, and control. Necrotizing enterocolitis was induced by enteral formula feeding and exposure to hypoxia after cold stress at 4°C and oxygen. The NEC + M group received 10 mg/kg M daily for 3 days after the first day of the NEC procedure. The pups were killed on the fourth day, and their intestinal tissues were harvested for biochemical and histopathologic analysis. Blood samples were also obtained from the pups., Results: The mortality rate and weight loss were highest in the NEC group. Malondialdehyde and protein carbonyl content were significantly increased, whereas superoxide dismutase and glutathione peroxidase were decreased in the NEC-treated pups. Melatonin prevented these changes, with these values being similar to control levels in the NEC + M group. Nitrate plus nitrite levels and serum tumor necrosis factor α and interleukin-1β were increased in the NEC group, and histopathologic injury score in the NEC group was significantly higher than that in the NEC + M group., Conclusion: Melatonin significantly reduced the severity of NEC in our study., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background/aims: Peritoneal adhesions, which occur most frequently after abdominal and pelvic operations, may lead to serious complications such as small intestine obstruction. In various studies, it has been shown that oxidative stress may play a role in the development of peritoneal adhesions, and studies carried out with antioxidants reported positive results. In the present study, the probable preventive role of alpha-lipoic acid, a strong antioxidant, in the development of peritoneal adhesions was investigated., Methods: Sixteen Sprague-Dawley male rats weighing 200-250 grams were employed. Under ketamine+xylazine anesthesia, on the antimesenteric aspect of the cecum, an adhesion model was formed with an incision, and half of the experimental animals were administered a daily single dose 100 mg/kg alpha-lipoic acid through orogastric gavage, and the other half formed the control group. Abdomens were opened 15 days later, and after adhesions were scored macroscopically, tissue samples were taken for evaluation of biochemical parameters., Results: In both adhesion scoring methods, a statistically significant decrease was found in the alpha-lipoic acid group compared to the control group (p<0.05). The decrease in adhesions was also confirmed by the significantly lower hydroxyproline levels in the alpha-lipoic acid group (p<0.05). In addition, alpha-lipoic acid decreased malondialdehyde levels in the adhesion region and prevented the increase in superoxide dismutase and glutathione peroxidase activities significantly (p<0.05)., Conclusions: It can be concluded from the findings of our study that alpha-lipoic acid decreased the development of adhesions in a peritoneal adhesion model and increased the quality of healing. These findings suggest that alpha-lipoic acid, already long used in various indications, may be tried clinically in patients about to undergo abdominal operations.

Objectives: Melatonin is a hormone which has many systemic effects in addition to its strong antioxidant properties. The aim of the present study was to investigate the difference between sytemic and topical administration of melatonin by forming a chronic wound model in rats whose release of basal melatonin was supressed by pinealectomy., Material and Methods: Experimental animals used in the study were divided into four equal groups: (i) a group of normal animals with wound formation (control), (ii) a group of animals who underwent pinelaectomy and wound formation (PINx), (iii) a group that underwent PINx + systemic melatonin administration, and (iv) a group that underwent PINx + topical melatonin administration. Fifteen days after pinealectomy, a bipediculed flap was formed on the back of the rats under anesthesia and then six excisional skin wounds were produced in all groups. Following the treatment that lasted 7 days, on day 8 the wound surface areas were measured and wound tissues were removed under anesthesia. In these tissues the levels of malondialdehit (MDA) and hydroxyproline (OH-proline) and the activities of superoxide dismutase(SOD) and glutathion peroxidase (GSH-Px) were measured., Results: In the PINx group, OH-prolin levels decreased significantly compared to the control group and wound surface areas increased. MDA levels increased compared to the control group, and SOD and GSH-Px decreased accordingly. Conversely, in two melatonin groups in which melatonin was administered systemically or topically MDA decreased while SOD ve GSH-Px enzymes increased., Conclusion: In conclusion, in the present study it was shown that wound healing was prolonged in experimental animals deprived of melatonin through pinealectomy. Melatonin exerts positive effects on wound healing, whether it is administered topically or systemically.

The present study was designed to evaluate whether the administration of s-methylisothiourea and melatonin has protective potential in intestinal ischemia/reperfusion injury. Forty male Sprague-Dawley rats were divided into five groups. Ileal specimens were obtained to determine the levels of malondialdehyde, protein carbonyl content, levels of antioxidant enzymes and evaluation of histologic changes. Combination of s-methylisothiourea and melatonin, led to a statistically significant increase in activities of antioxidant enzymes with a decrease in malondialdehyde and protein carbonyl content and intestinal mucosal injury scores. It was shown; combination of SMT and melatonin may exert more promised results.

Objective: Acute intestinal ischemia reperfusion (I/R) injury affects not only the intestines but also remote organs due to pro-inflammatory and tissue injurious factors. Thus, we aimed to investigate the roles of melatonin (a powerful antioxidant) and 1400W (a strong inhibitor of inducible nitric oxide) in a rat intestinal I/R injury model, since oxidative and nitrosative injury are believed to be the major causes., Methods: A total of 56 Wistar albino rats were used, with seven rats in each group. After I/R induction in the intestines by clamping/unclamping the superior mesenteric artery, we measured malondialdehyde, superoxide dismutase, glutathione peroxidase, nitric oxide, and 3-nitrotyrosine levels in lung, kidney, and liver tissues (to evaluate remote organ injury) as well as in the intestines. Study groups received melatonin, 1400W or both to examine the roles of these molecules in the pathogenesis of injury following I/R., Results: Melatonin and 1400W had an ameliorating effect on both oxidative and nitrosative stress in the intestine and the lung against mesenteric I/R injury in rats. Moreover, each of these two agents had an inhibitory effect on oxidative injury and histopathological changes in the intestine and the lung. Furthermore, the combination of both agents (melatonin and 1400W) was more effective than either of the agents alone (P < 0.05)., Conclusion: Melatonin and 1400W, either alone or in combination, were efficient in ameliorating experimental I/R injury of the intestines.

Background and Aim: Intra-abdominal adhesions are important postoperative complications following abdominal surgery. The adhesions that develop form the basis of more advanced pathology such as intestinal obstruction or infertility. Melatonin is secreted from the pineal gland in a circadian pattern; this molecule has potent antioxidant characteristics and has beneficial effects in many models of inflammation. The aim of this study was to evaluate the effects of melatonin on peritoneal adhesions created in rats., Methods: A total of 28 Sprague-Dawley male rats were used and divided into four groups. In the first phase of the study, pinealectomy (PINX) was performed on half the animals. An incision was made and sutured in the cecum of all experimental animals in all groups 15 days after the PINX procedure. Some animals were given melatonin orally at a dose of 5 mg/kg daily following the adhesion operation and continued for 15 days. The rats were anesthetized and the abdomen opened after the 15th day (on day 30 of the study). After adhesion scoring based on macroscopic inspection, tissue samples were obtained from the sutured region of the cecum to measure malondialdehyde and hydroxyproline., Results: Peritoneal adhesion density was significantly higher in the PINX group compared to the control animals; exogenously administered melatonin significantly reduced adhesion formation. The degree of adhesion was also significantly lower in the intact rats given melatonin compared to the control group., Conclusion: Antioxidant activity increases in the oxidative process. We conclude that melatonin may be an important molecule in preventing peritoneal adhesions.

Background and Aim: Reactive oxygen species generated during reperfusion of the tissue are known to play an important role in the basic pathophysiology of ischemia/reperfusion (I/R) injury. The aim of this study was to investigate and compare the protective effects of three sulfide-based antioxidants, N-acetylcysteine (NAC), erdosteine (ERD), and alpha-lipoic acid (LA), on I/R injury of the small intestine tissue., Methods: Forty male Sprague-Dawley rats weighing between 100-150 g were divided into five groups (n = 8 for each): control (sham operated), I/R, I/R + NAC, I/R + ERD, and I/R + LA. Intestinal ischemia was provided by occluding the superior mesenteric artery via a special microvascular clamp; ischemia for 30 min and reperfusion for 3 days were carried out. Ileal specimens were obtained to determine the tissue levels of malondialdehyde (MDA), protein carbonyl contents (PCO), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities and histological changes., Results: The rats subjected to intestinal I/R exhibited an increase in tissue MDA and PCO; the levels could hardly be ameliorated in the treatment groups. SOD and GPx activities were significantly decreased in the I/R group, whereas their reduction was less expressed in the treatment groups. Additionally, the histopathological injury scores of the disulfide-treated groups were lower than those of the I/R group., Conclusion: All of the sulfhydryl-containing antioxidants used in this study exhibited a significant role in attenuating intestinal I/R injury; however, the outcome of the LA-treated group was significantly marked than that of the others.

Oxidative stress plays a key role in the pathogenesis of aging and many metabolic diseases; therefore, an effective antioxidant therapy would be of great importance in these circumstances. Nutritional, environmental, and chemical factors can induce the overproduction of the superoxide anion radical in both the cytosol and mitochondria. This is the first and key event that leads to the activation of pathways involved in the development of several metabolic diseases that are related to oxidative stress. As oxidation of essential molecules continues, it turns to nitrooxidative stress because of the involvement of nitric oxide in pathogenic processes. Once peroxynitrite forms, it damages via two distinctive mechanisms. First, it has direct toxic effects leading to lipid peroxidation, protein oxidation, and DNA damage. This mechanism involves the induction of several transcription factors leading to cytokine-induced chronic inflammation. Classic antioxidants, including vitamins A, C, and E, have often failed to exhibit beneficial effects in metabolic diseases and aging. Melatonin is a multifunctional indolamine that counteracts virtually all pathophysiologic steps and displays significant beneficial actions against peroxynitrite-induced cellular toxicity. This protection is related to melatonin's antioxidative and antiinflammatory properties. Melatonin has the capability of scavenging both oxygen- and nitrogen-based reactants, including those formed from peroxynitrite, and blocking transcriptional factors, which induce proinflammatory cytokines. Accumulating evidence suggests that this nontoxic indolamine may be useful either as a sole treatment or in conjunction with other treatments for inhibiting the biohazardous actions of nitrooxidative stress.

Introduction: We investigated the roles of melatonin (a powerful antioxidant, iNOS inhibitor, and a scavenger of peroxynitrite) and 1400W (a strong and selective inhibitor of inducible nitric oxide) on renal dysfunction and injury induced by ischemia/reperfusion (I/R) of rat kidney, since oxidative and nitrosative injury are believed to be the major causes., Materials and Methods: Thirty-two male Sprague-Dawley rats were divided into four groups of sham-operated, I/R, I/R + Melatonin and I/R + 1400W. Rats were given either melatonin (10 mg/kg) or 1400W (10 mg/kg) in the I/R + Melatonin and I/R + 1400W groups respectively at 6 h prior to ischemia and at the beginning of reperfusion via intraperitoneal route. I/R injury was induced by 60 min of bilateral renal ischemia followed by 6 h of reperfusion. After reperfusion, kidneys and blood were obtained for histopathologic and biochemical evaluation., Results: Melatonin and 1400W had an ameliorative effect on both oxidative and nitrosative stress in the kidneys against renal I/R injury in rats. In addition, melatonin significantly reduced elevated nitro-oxidative stress product, restored decreased antioxidant enzymes and attenuated histological alterations when compared with 1400W., Conclusions: Both Melatonin and 1400W were efficient in ameliorating experimental I/R injury of the kidneys. Moreover, melatonin was more effective than 1400W possibly through inhibiting iNOS as well as scavenging free oxygen radicals and peroxynitrite.

Melatonin (N-acetyl-5-methoxytryptamine) has been detected in a number of plant species. Indeed, there exists evidence that this classically-considered animal indole is actually both synthesized in and taken up by plants. Among the actions that melatonin may carry out in plant tissues, its role as an antioxidant or growth promoter is most strongly supported by the experimental evidence. Other suggested functional implications include the co-ordination of photoperiodic responses and regulation of plant reproductive physiology, defence of plant cells against apoptosis induced by harsh environmental conditions, its participation as a free radical scavenging agent and/or up-regulator of certain protective enzymes in the senescent process. This review presents a detailed summary of the investigations that have been performed to date in the plant melatonin (phytomelatonin) field. The purpose of this summary is to bring the reader up to date on what is known about melatonin in plants and to encourage plant scientists to investigate this novel research topic; this would certainly assist in solving the numerous questions that still remain regarding the role of melatonin in plants.

The purpose of this brief review is to introduce the reader to the vast amount of published literature related to the free radical scavenging and antioxidative activity of melatonin. However, this review summarizes only a few of the many conditions in which melatonin has been found to be protective against oxidative/nitrosative damage. Melatonin ameliorates the extensive free radical-mediated damage that ensues following exposure to a wide variety of environmental insults. Concisely reviewed in this report are the protective effects of melatonin against toxic prescription drugs, neural toxins, herbicides and metals. The findings have clear implications for the utility of melatonin in toxicology.

Among the most readily available chemical warfare agents, sulfur mustard (SM) has been the most widely used chemical weapon. The toxicity of SM as an incapacitating agent is of much greater importance than its ability to cause lethality. Oxidative stress is the first and key event in the pathogenesis of SM toxicity. The involvement of inducible nitric oxide (iNOS) in SM toxicity, however, also leads to elevated nitrosative stress; thus, the damage caused by SM is nitro-oxidative stress because of peroxynitrite (ONOO-) production. Once ONOO- is formed, it activates nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) leading to pro-inflammatory gene expression thereby promoting inflammation; additionally, ONOO- directly exerts harmful effects by damaging all biomolecules including lipids, proteins and DNA within cells. DNA damage is sensed by an important DNA repair enzyme, poly (ADP-ribose) polymerase (PARP); this enzyme repairs molecular damage by using nicotinamide adenine dinucleotide (NAD+) as a substrate. Over-activation of PARP, due to severe DNA damage, consumes vast amounts of the respiratory coenzyme NAD+ leading to a cellular energy crisis. This pathophysiologic mechanism eventually results in cellular dysfunction, apoptosis or necrosis. Therefore, classic antioxidants may have limited beneficial effects on SM toxicity. Melatonin is a multifunctional indolamine which counteracts virtually all pathophysiologic steps and displays significant beneficial effects against ONOO--induced cellular toxicity. Melatonin has the capability of scavenging both oxygen and nitrogen-based reactants including ONOO- and blocking transcriptional factors which induce pro-inflammatory cytokines. The delayed toxicity of SM, however, currently has no mechanistic explanation. We propose that epigenetic aberrations may be responsible for delayed detrimental effects of mustard poisoning. Therefore, as a putative epigenetic modulator, melatonin may also be beneficial to subjects with delayed toxicity of SM.

N-acetyl-5-methoxytryptamine (melatonin) is an endogenous indoleamine produced by all vertebrate organisms. Its production in the pineal gland has been extensively investigated but other organs also synthesize this important amine. Melatonin's functions in organisms are diverse. The actions considered in the current review relate to its ability to function in the reduction of oxidative stress, i.e., molecular damage produced by reactive oxygen and reactive nitrogen species. Numerous publications have now shown that not only is melatonin itself an efficient scavenger of free radicals and related reactants, but so are its by-products cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and others. These derivatives are produced sequentially when each functions in the capacity of a free radical scavenger. These successive reactions are referred to as the antioxidant cascade of melatonin. That melatonin has this function within cells has been observed in studies employing time lapse conventional, confocal and multiphoton fluorescent microscopy coupled with the use of appropriate mitochondrial-targeted fluorescent probes. The benefits of melatonin and its metabolites have been described in the brain where they are found to be protective in models of Parkinson's disease, Alzheimer's disease and spinal cord injury. The reader is reminded, however, that data not covered in this review has documented beneficial actions of these amines in every organ where they have been tested. The outlook for the use of melatonin in clinical trials looks encouraging given its low toxicity and high efficacy.

Introduction: The enzyme poly(adenosine diphosphate-ribose) polymerase affects the repair of DNA in damaged cells. However, its activation in damaged cells can lead to adenosine triphosphate depletion and death. This study was designed to investigate the efficacy of 3-amino benzamide (3-AB), a poly(adenosine diphosphate-ribose) polymerase inhibitor, on the prevention of esophageal damage and stricture-formation development after esophageal caustic injuries in rat., Materials and Methods: Forty-five rats were allocated into 3 groups: sham-operated, untreated, and treated groups. Caustic esophageal burn was created by instilling 15% NaOH to the distal esophagus. The rats were left untreated or treated with 3-AB 10 mg/kg per day intraperitoneally. All rats were killed on the 28th day. Efficacy of the treatment was assessed by measuring the stenosis index and histopathologic damage score and biochemically by determining tissue hydroxyproline content, superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), and protein carbonyl content (PCC) in esophageal homogenates., Results: Treatment with 3-AB decreased the stenosis index and histopathologic damage score seen in caustic esophageal burn rats. Hydroxyproline level was significantly higher in the untreated group as compared with the group treated with 3-AB. Caustic esophageal burn increased MDA and PCC levels and also decreased SOD and GPx enzyme activities. On the contrary, 3-AB treatment decreased the elevated MDA and PCC levels and also increased the reduced SOD and GPx enzyme activities., Conclusion: 3-Amino benzamide has a preventive effect in the development of fibrosis by decreasing tissue damage and increasing the antioxidant enzyme activity in an experimental model of corrosive esophagitis in rats.

Background: Oxidative stress plays a role in the mechanism of chronic kidney disease (CKD), and antioxidant regimes are regarded as promising treatment modalities. We compared the effects of cilazapril, simvastatin, and hyperbaric oxygen (HBO) treatment on proteinuria and on oxidative stress in adriamycine (ADR)-induced proteinuria., Methods: Seventy male Sprague-Dawley rats were housed, and 60 were injected with ADR to induce nephrosis. After the stabilization of proteinuria, rats were treated for 6 weeks with simvastatin (n = 10, 4 mg/kg/day), cilazapril (n = 10, 10 mg/kg/day), HBO (n = 10, 2.8 athmosphere absolute, 90 min/daily), HBO + cilazapril (n = 10), HBO + simvastatin (n = 10), and vehicle (n = 10). After euthanization at 12 weeks, protein carbonyl (PCO), superoxide dismutase (SOD), and glutathion peroxidase (GPx) levels were analyzed from tissues. The histological alterations in the kidneys were determined by semiquantitative scoring., Results: Protein carbonyl (PCO) levels were higher (p < 0.001), and the GPx and SOD levels were lower (p < 0.001 for all) in the nephrotic rats. Proteinuria was correlated to PCO (r = 0.483), GPx (r = -0.686), or SOD (r = -0.620) (p < 0.001 for all). Superoxide dismutase (SOD) (beta = -0.381, p = 0.02) and GPx (beta = -0.509, p < 0.001) were independently related to proteinuria levels. Both cilazapril and simvastatin significantly improved GPx, SOD, PCO, and proteinuria. When HBO was combined with either drug, the above markers further improved (p < 0.001). Both regimens caused distinct histological features, while the combination of HBO made much significant histological improvement., Conclusion: Both cilazapril and simvastatin regimens improve oxidative stress and proteinuria, while the effects significantly increase with the combination of HBO treatment. HBO seems to be a candidate antioxidant strategy in glomerular diseases.

Introduction: Several natural products have been reported to have beneficial effects on ischemia/reperfusion (I/R) injury, particularly from a preventative perspective. Therefore, this study was designed to investigate the efficiency of proanthocyanidin (PA), a natural product derived from grape seed, on renal dysfunction and injury induced by I/R of rat kidney., Materials and Methods: Twenty-four male Sprague-Dawley rats were divided into three groups: sham-operated, I/R, I/R+PA. Rats were given PA (100 mg/kg/day peroral) 7 days prior to I/R. All rats except sham-operated underwent 60 min of bilateral renal ischemia followed by 6 h of reperfusion. After reperfusion, kidneys and blood were obtained for evaluation. Superoxide dismutase, glutathione peroxidase, malondialdehyde, protein carbonyl content, and nitrite/nitrate level (NO(x)) were determined in the renal tissue. Serum creatinine (S(Cr)), blood urea nitrogen (BUN), and aspartate aminotransferase (AST) were determined in the blood. Additionally, renal sections were used for histological grade of renal injury., Results: PA significantly reduced the I/R-induced increases in S(Cr), BUN, and AST. In addition, PA markedly reduced elevated oxidative stress product, restored decreased antioxidant enzymes, and attenuated histological alterations. Moreover, PA attenuated the tissue NO(x), levels indicating reduced NO production., Conclusions: The pretreatment of rats with PA reduced the renal dysfunction and morphological changes, ameliorated cellular injury, and restored renal antioxidant enzymes caused by renal I/R.

Purpose: Reactive oxygen species (ROS) and reactive nitrogen species (RNS), generated during tissue reperfusion, are characteristic of ischemia/reperfusion (I/R) injury. We conducted this study to evaluate the protective effect of alpha-lipoic acid (alpha-LA) and ebselen against intestinal I/R injury., Methods: Forty Sprague-Dawley rats were divided into five groups: a sham-operated group; an I/R group, subjected to intestinal ischemia for 45 min and reperfusion for 3 days; an I/R+alpha-LA group; an I/R+ebselen group; and an I/R+alpha-LA+ebselen group. We collected ileal specimens, to measure the tissue levels of malondialdehyde (MDA), protein carbonyl content (PCC), superoxide dismutase (SOD), and glutathione peroxidase (GPx), and to evaluate the histologic changes., Results: There was a significant decrease in SOD and GPx levels, with an increase in MDA and PCC levels and intestinal mucosal injury in the intestinal I/R group (P<0.05). Superoxide dismutase and GPx levels were significantly higher, MDA and PCC levels were significantly lower, and intestinal injury was significantly less severe in the I/R+alpha-LA+ebselen group than in the I/R group (P<0.05). Although shortened villi and epithelial lifting were seen in the I/R group, only slight mucosal injury was seen in the treatment groups., Conclusion: alpha-Lipoic acid and ebselen played an important role in attenuating I/R injury of the intestine by scavenging ROS and RNS.

The cytotoxic mechanism of mustards has not been fully elucidated; recently, we reported that reactive oxygen species, nitric oxide [produced by inducible nitric oxide synthase (iNOS)] and peroxynitrite are involved in the pathogenesis and responsible for mustard-induced toxicity. Melatonin, a potent antioxidant molecule, acts as an iNOS inhibitor and a peroxynitrite scavenger. Using the prototypic nitrogen mustard (mechlorethamine/HN2) as a model and based on its known cytotoxic mechanisms, the present study was performed to test melatonin for its capability in protecting the lungs of injured male Wistar rats. Lung mustard toxicity was induced via an intratracheally injection of HN2 (0.5mg/kg) dissolved in saline (100microl). Control animals were injected the same amount of saline only. Melatonin was administered intraperitoneally with two different doses (20mg/kg or 40mg/kg) beginning 1h before HN2 application and continued every 12h for six replications. Forty-eight hours after the last melatonin injection, the animals were sacrificed and their lungs were taken for further assay, i.e., malondialdehyde (MDA) levels, and superoxide dismutase (SOD), glutathione peroxidase (GPx) and iNOS activity. Additionally their urine was collected for nitrite-nitrate (NO(x)) analysis. HN2 injection caused increased iNOS activity and MDA levels in lung tissue and NO(x) values in urine; lung GPx activity was significantly depressed. Melatonin restored all of these oxidative and nitrosative stress markers in a dose-dependent manner. In conclusion, the results of study provide evidence that melatonin may have the ability to reduce mustard-induced toxicity in the lungs.

In addition to its beneficial effects, hyperbaric oxygen (HBO) exposure causes some detrimental effects via oxidative stress. Previous experimental studies showed that melatonin is a useful agent to block single session HBO-induced oxidative stress. In the present study, we investigated the antioxidant effect of exogenously administered as well as endogenously produced melatonin in lung and brain tissues of rats exposed to long term HBO. The HBO procedure was set as daily exposures to 2.5 ATA of oxygen for 1 hr and a total of 10 sessions. Twenty-eight male Sprague-Dawley rats were divided into four groups as follows: control, daytime HBO, daytime HBO plus melatonin (5 mg/kg), nighttime HBO. Tissue oxidative/antioxidant status was examined by determining the protein carbonyl content as a criteria for oxidative stress and the activities of the antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). HBO exposure for 10 days caused significant increases in protein carbonyl content and SOD levels of lung and brain, but GSH-Px activities remained unaffected. The increases in protein carbonyls were blocked by exogenously administered melatonin and in part by nighttime exposure to darkness whereas the increase of SOD activity was only impeded by endogenously produced melatonin in brain tissue. Lung SOD activity was augmented by endogenous melatonin. In conclusion, melatonin blocks long-term HBO-induced cumulative oxidative stress as indicated changes in protein carbonyls. Both exogenously injected and physiologically secreted melatonin has this potential. The effects of HBO-exposure and melatonin on the activities of the antioxidative enzymes are less clear.

Cyclophosphamide (CP) is widely used, alone or in combination with other chemotherapeutic agents, for treatment of neoplastic diseases. Its urotoxicity may cause dose-limiting side-effects, for example hemorrhagic cystitis. The agent most often used to prevent this side-effect is mesna (2-mercaptoethane sulfonate). Overproduction of reactive oxygen species during inflammation is one reason for possible urothelial injury. The aim of this study was to evaluate whether combinations of quercetin and epigallocatechin 3-gallate (EGCG), flavonoid antioxidants and mesna could prevent cystitis induced by cyclophosphamide, better than mesna alone. A total of 38 male Sprague-Dawley rats were divided into five groups. Four groups received single dose of CP (100 mg kg(-1)) intraperitoneally at the same time. Group 2 received CP only, group 3 received mesna (3 x 21.5 mg kg(-1)), group 4 received a single dose of mesna+EGCG (2 x 20 mg kg(-1)), and group 5 received a single dose of mesna+quercetin (2 x 20 mg kg(-1)), before and after CP injection. Group 1 (not treated) served as control. CP injection alone resulted in severe cystitis. Mesna resulted in some, but not full, protection against CP toxicity. Quercetin and catechine, together with mesna, resulted in full protection against CP toxicity, on the basis of histopathology of the urinary bladder. It was concluded that oxidants might be important in the pathogenesis of CP-induced cystitis, and that flavonoid antioxidants, used in addition to mesna, may help to ameliorate bladder damage.

The aim of the present study was the evaluation of possible protective effects of quercetin (QE) against beta-cell damage in experimental streptozotocin (STZ)-induced diabetes in rats. STZ was injected intraperitoneally at a single dose of 50 mg kg(-1) for diabetes induction. QE (15 mg kg(-1) day, intraperitoneal (i.p.) injection) was injected for 3 days prior to STZ administration; these injections were continued to the end of the study (for 4 weeks). It has been believed that oxidative stress plays a role in the pathogenesis of diabetes mellitus (DM). In order to determine the changes of cellular antioxidant defense system, antioxidant enzymes such as glutathione peroxidase (GSHPx), superoxide dismutase (SOD) and catalase (CAT) activities were measured in pancreatic homogenates. Moreover we also measured serum nitric oxide (NO) and erythrocyte and pancreatic tissue malondialdehyde (MDA) levels, a marker of lipid peroxidation, if there is an imbalance between oxidant and antioxidant status. Pancreatic beta-cells were examined by immunohistochemical methods. STZ induced a significant increase lipid peroxidation, serum NO concentrations and decreased the antioxidant enzyme activity. Erythrocyte MDA, serum NO and pancreatic tissue MDA significantly increased (P < 0.05) and also the antioxidant levels significantly decreased (P < 0.05) in diabetic group. QE treatment significantly decreased the elevated MDA and NO (P < 0.05), and also increased the antioxidant enzyme activities (P < 0.05). QE treatment has shown protective effect possibly through decreasing lipid peroxidation, NO production and increasing antioxidant enzyme activity. Islet cells degeneration and weak insulin immunohistochemical staining was observed in STZ induced diabetic rats. Increased staining of insulin and preservation of islet cells were apparent in the QE-treated diabetic rats. These findings suggest that QE treatment has protective effect in diabetes by decreasing oxidative stress and preservation of pancreatic beta-cell integrity.

Purpose: The aim of this study was to evaluate whether combination of antioxidants and mesna may prevent cystitis induced by cyclophosphamide better than mesna alone., Materials and Methods: A total of 46 male Sprague-Dawley rats were divided into six groups. Five groups received single dose of cyclophosphamide (CP, 100 mg/kg) intraperitoneally with the same time intervals: group 2 received CP only, group 3 received mesna (21.5 mg/kg for three times), group 4 beta-carotene (20 mg/kg for two times) and mesna, group 5 received alpha-tocopherol (20 mg/kg for two times) and mesna, and group 6 received melatonin (5 mg/kg for two times) and mesna on the day of CP injection. Group 1 served as control., Results: CP injection resulted in severe cystitis. Mesna has showed meaningful but not full protection against CP toxicity. Although beta-carotene did not show any additional beneficial effect when combined with mesna, alpha-tocopherol and especially melatonin with mesna resulted full protection that the pathologist, blinded to the slides, could not differ from sham control., Conclusion: Oxidants may be important in the pathogenesis of CP-induced cystitis. Melatonin and alpha-tocopherol may help to ameliorate bladder damage along with other drugs such as mesna and diuretics.

OBJECTIVE: Contrast-induced nephropathy (CIN) is a common complication of diagnostic or interventional procedures that may arise from administration of intravascular contrast media. Recent studies have reported the thiol-disulfide ratio as a novel oxidative stress marker. Therefore, we investigated the role of thiol levels in predicting CIN in patients with ST-segment elevation myocardial infarction (STEMI) who had undergone primary percutaneous coronary intervention (PCI). METHODS: A total of 302 patients were enrolled in the study. CIN was defined as an increase in serum creatinine concentration =0.5 mg/dL compared with the admission value or a >25% relative rise during the first 48-72 hours after the procedure. To evaluate the relationship between thiol levels and CIN, the patients were divided into a CIN group and a non-CIN group. RESULTS: CIN occurred in 44 (15%) patients. Native thiol (274.8±84.7 µmol/L vs. 220.8±97.1 µmol/L, p=0.001) and total thiol (305.4±89.7 µmol/L vs. 260.1±102.1 µmol/L, p=0.009) levels were higher in patients within the non-CIN group. Disulfide (15.8±6.6 µmol/L vs. 19.6±8.4 µmol/L, p=0.002) levels, and mean disulfide/total thiol ratios (8.4±3.7 vs. 5.9±3.1, p=0.001) were higher in patients with CIN (+) group. In univariate analysis, the initial native thiol, total thiol, disulfide levels, and disulfide/total thiol ratio were found to have prognostic significance in the development of CIN. In the multivariate regression analysis, only the disulfide/total thiol ratio (OR=1.190; 95% CI: 1.090-1.300; p=0.001) was significantly and independently associated with CIN. The cutoff value of the disulfide/total thiol ratio to predict CIN on admission in patients with STEMI who underwent primary PCI was 7, with a sensitivity of 68.2% and a specificity of 79.8%. CONCLUSION: Our results suggest that thiol/disulfide homeostasis could be a good biochemical risk marker for CIN in STEMI patients who underwent primary PCI. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Medical Biochemistry is the property of Society of Medical Biochemists of Serbia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: This study was designed to investigate the possible beneficial effects of medical ozone therapy (OT), known as an immunomodulator and antioxidant, on the renal function, morphology, and biochemical parameters of oxidative stress in kidneys subjected to ischemia/reperfusion injury (IRI). Materials and methods: Thirty male Sprague-Dawley rats were classified into three groups: control, renal IRI, and renal IRI + OT. The IRI group was induced by bilateral renal ischemia for 60 min, followed by reperfusion for 6 h. After reperfusion, the kidneys and blood of rats were obtained for histopathologic and biochemical evaluation. Results: Renal IRI increased the tissue oxidative stress parameters (lipid peroxidation, protein oxidation, and nitrite plus nitrate) and decreased the antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase). The serum neopterin levels showed correlation with oxidative stress parameters. All these parameters were brought to control values in the treatment group. Histopathologically, the kidney injury in the treatment group was significantly lesser than in the renal IRI group. Conclusions: Our results clearly showed that OT has beneficial effect to protect kidney against IRI. The serum neopterin levels might be used as a marker to detect the degree of renal IRI. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: After ingestion of caustic material, tissue damage is caused by reactive oxygen species and reactive nitrogen species such as peroxynitrite. Mercaptoethylguanidine (MEG) is a well-known scavenger of peroxynitrite. This study was designed to determine whether MEG has a beneficial effect on caustic esophageal injury. Materials and Methods: Forty-five rats were allocated into 3 groups: sham-operated, untreated, and treated groups. Caustic esophageal burn was created by instilling 15% NaOH in the distal esophagus. The rats were left untreated or treated with 10 mg/kg per day MEG intraperitoneally for 5 days. All rats were killed at 28 days. Efficacy of the treatment was assessed both histopathologically and biochemically. Results: Of 15 rats, 6 (40%) died in the untreated group, and only 1 (7%) rat died in the treated group. The stenosis index (SI) and the histopathologic damage score were significantly lower in the MEG treatment group than the untreated group, which showed a correlation with tissue hydroxyproline level. In the untreated group, tissue oxidative stress parameters (malondialdehyde and protein carbonyl content) were significantly higher; and antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase) were significantly lower. Administration of MEG ameliorated oxidative stress parameters and antioxidant enzyme activities. Urinary nitrate and nitrite levels increased in the treated and untreated groups in the first 3 days, suggesting increased nitrosative stress; but at the fourth day, nitrate and nitrite level reached control values in the treated group. Conclusion: Peroxynitrites play an important role in the healing process of caustic esophagitis. As a peroxynitrites scavenger, MEG potentially might be a useful adjuvant agent in the treatment of esophageal caustic burn by modulating the antioxidant defense mechanism. [Copyright &y& Elsevier]

Context: Despite its known benefits, hyperbaric oxygen (HBO) is also reported to enhance the production of reactive oxygen species and can cause oxidative stress in several tissues. Previous studies had shown that HBO-induced oxidative stress is directly proportional to both its exposure pressure and duration. Nevertheless, these studies were usually performed with single-session HBO exposure but its clinical use commonly depends on long-term exposure periods. Objective: To clarify the oxidative effect of long-term repetitive HBO in the lung tissue of rats. Materials and methods: Male Sprague-Dawley rats were divided into six study groups exposed to consecutive HBO sessions (2.8 atm/90 min) for 5, 10, 15, 20, 30, and 40 days. Animals were sacrificed 24 h after the last HBO session. An additional control group was set to obtain normal data. Lung malondialdehyde (MDA) and carbonylated protein (PCC) levels were determined as measures of oxidative stress along with the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase. Results: None of the measured parameters showed any changes among the groups exposed to 5--15 HBO sessions. However, MDA, PCC, and SOD were found to be significantly increased in the 20 to 40 session groups. Discussion and conclusion: These results indicate that repetitive treatment with HBO may cause oxidative stress in critical tissues including the lung. Although HBO-mediated free radicals are accepted to be responsible for the benefits of this therapeutic modality, especially in cases with prolonged exposure, possible injurious effects of supranormal values of bio-oxidative products need to be considered. [ABSTRACT FROM AUTHOR]

Copyright of Gulhane Medical Journal is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Melatonin is a molecule present in a multitude of taxa and may be ubiquitous in organisms. It has been found in bacteria, unicellular eukaryotes, macroalgae, fungi, plants and animals. A primary biological function of melatonin in primitive unicellular organisms is in antioxidant defence to protect against toxic free radical damage. During evolution, melatonin has been adopted by multicellular organisms to perform many other biological functions. These functions likely include the chemical expression of darkness in vertebrates, environmental tolerance in fungi and plants, sexual signaling in birds and fish, seasonal reproductive regulation in photoperiodic mammals, and immunomodulation and anti-inflammatory activity in all vertebrates tested. Moreover, its waning production during aging may indicate senescence in terms of a bio-clock in many organisms. Conversely, high melatonin levels can serve as a signal of vitality and health. The multiple biological functions of melatonin can partially be attributed to its unconventional metabolism which is comprised of multi-enzymatic, pseudo-enzymatic and non-enzymatic pathways. As a result, several bioactive metabolites of melatonin are formed during its metabolism and some of the presumed biological functions of melatonin reported to date may, in fact, be mediated by these metabolites. The changing biological roles of melatonin seem to have evolved from its primary function as an antioxidant. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Necrotizing enterocolitis (NEC) remains a major cause of morbidity and death in neonates. Evidence suggests that an imbalance between activated proinflammatory response with inadequate antiinflammatory protection results in NEC. Ozone has been proposed as an antioxidant enzyme activator, immunomodulator, and cellular metabolic activator. Therefore, this study was designed to investigate whether medical ozone therapy is effective on neonatal rat model of NEC. Materials and Methods: Thirty-eight newborn Sprague-Dawley pups were randomly divided into 3 groups of NEC, NEC + ozone, and control (left to breast feed). Necrotizing enterocolitis was induced by enteral formula feeding and exposure to 100% carbon dioxide inhalation for 10 minutes after +4°C cold exposures for 5 minutes and 97% oxygen for 5 minutes 2 times daily. The NEC + ozone group received 0.7 mg/kg per day ozone/oxygen mixture intraperitoneally for a total of 3 days after first day of NEC procedure. The pups were killed at fourth day, and their intestinal tissues were harvested for biochemical and histopathologic analysis. Blood sample from pups were also obtained. Results: The mortality rate and the weight loss were significantly higher in NEC group than control and treatment groups. Oxidative stress markers (malondialdehyde and protein carbonyl content) significantly increased and antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase) were significantly decreased in NEC group. All these biochemical changes were ameliorated in NEC + ozone group. Nitrate plus nitrite levels and serum tumor necrosis factor α were elevated in NEC group and reduced in treatment group. In addition, histopathologic injury score of NEC group was significantly higher than NEC + ozone group. Conclusion: Ozone treatment significantly reduced the severity of NEC by modulating antioxidative defense and antiinflammatory protection in our experimental animal model. [Copyright &y& Elsevier]

Despite many years of research into chemical warfare agents, cytotoxic mechanisms induced by mustards are not well understood. Reactive oxygen and nitrogen species (ROS and RNS) are likely to be involved in chemical warfare agents induced toxicity. These species lead to lipid peroxidation, protein oxidation, and DNA injury, and trigger many pathophysiological processes that harm the organism. In this article, several steps of pathophysiological mechanisms and possible ways of protection against chemical warfare agents have been discussed. In summary, pathogenesis of mustard toxicity is explained by three steps: (1) mustard binds target cell surface receptor, (2) activates intracellular ROS and RNS leading to peroxynitrite (ONOO−) production, and (3) the increased ONOO− level damages organic molecules (lipids, proteins, and DNA) leading to poly(adenosine diphosphate-ribose) polymerase (PARP) activation. Therefore, protection against mustard toxicity could also be performed in these ways: (1) blocking of cell surface receptor, (2) inhibiting the ONOO− production or scavenging the ONOO− produced, and (3) inhibiting the PARP, activated by ONOO− and hydroxyl radical (OH•) induced DNA damage. As conclusion, to be really effective, treatment against mustards must take all molecular mechanisms of cytotoxicity into account. Combination of several individual potent agents, each blocking one of the toxic mechanisms induced by mustards, would be interesting. Therefore, variations of combination of cell membrane receptor blockers, antioxidants, nitric oxide synthase inhibitors, ONOO− scavengers, and PARP inhibitors should be investigated. [ABSTRACT FROM AUTHOR]

1. Hyperbaric oxygen (HBO) is a widely used treatment modality in many diseases. A known side-effect of HBO is the production of reactive oxygen species (ROS). Many antioxidants, such as vitamins C and E, riboflavin and selenium, have been used successfully to scavenge the ROS produced by HBO administration. 2. The aim of the present study was to determine whether melatonin, a newly discovered anti-oxidant, has a protective effect against the overproduction of ROS produced by HBO in rat brain tissue. 3. Seventy male Sprague-Dawley rats were divided into seven groups as follows: 1, daytime control; 2, daytime HBO; 3, melatonin; 4, daytime HBO plus melatonin; 5, night-time control; 6, night-time HBO; and 7, night-time HBO under light exposure. 4. Hyperbaric oxygen was administered at 303 kPa for 120 min. Melatonin was injected at a dose of 10 mg/kg, i.p. Brain malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels were measured to elucidate oxidant status. 4. The MDA and SOD levels of groups 2 and 7 increased significantly. Exogenous (group 4) and endogenous (group 6) melatonin protected against HBO-induced lipid peroxidation. Exogenously administered melatonin (groups 3 and 4) had increased levels of the anti-oxidant enzymes SOD and GPx, 5. In conclusion, HBO caused oxidative stress and melatonin exhibited protective effects. Both endogenously produced and exogenously administered melatonin were found to be effective. [ABSTRACT FROM AUTHOR]

Cyclophosphamide (CP), an alkylating antineoplastic agent, has potential urotoxicity including causing hemorrhagic cystitis (HC). HC is now accepted as a non-infectious inflammation and the pathogenesis of HC includes cytokine production which leads to inducible nitric oxide synthase (iNOS) induction. Moreover, overproduction of reactive oxygen species (ROS) during inflammation leads to extensive oxidative stress, cellular injury and apoptosis/necrosis via several mechanisms. Based on these facts, the aim of this study was to evaluate the protective effects of melatonin as an antioxidant, iNOS inhibitor and peroxynitrite scavenger against CP-induced urinary bladder damage. A total of 30 male Sprague–Dawley rats were divided into four groups. Three groups received a single dose of CP (100 mg/kg) intraperitoneally with the same times. Group 2 received CP only, group 3 received 5 mg/kg/day and group 4 received 10 mg/kg/day melatonin before and the day after CP administration. Group 1 served as the control. Increased iNOS induction, bladder malonyldialdehyde (MDA) levelsand urinary nitrite–nitrate excretion were encountered in the CP-only group leading to severe cystitis. Melatonin exhibited significant protection against CP-induced cystitis by diminishing bladder oxidative stress and blocking iNOS and peroxynitrite production. Oxidants may have a major role in the pathogenesis of CP-induced cystitis and iNOS is an important mediator leading to peroxynitrite production. Melatonin ameliorates bladder damage induced by CP. [ABSTRACT FROM AUTHOR]

Objective: To prolong the lifetime and improve the life quality is very important apart from curing the cancer which is among the first three leading cause of death in a variety of region in the world. Cancer could be summarized as the irregular and immortal life cycle of the cells through the imbalance of genes which controls the normal life cycle. By this way they harm the homeostasis. Many scientists have been continuously working on a variety of plans to cure the cancer. Melatonin is currently under investigation as an alternative among these plans. Main findings: The efficacies of pineal gland, the biological significance of that is known for thousand of years and its secretory product melatonin have systematically studied at the beginning of 20th century for the first time. Since then, enormous studies have been conducted in terms of its direct anti-cancer efficacy as well as a chronobiological regulator, antioxidant and immune modulator. Apart from the efficacy of melatonin on variety of cancers, when used along with classical cancer treatment protocols, researches have shown that melatonin boosts general conditions, clinical outcome and life span. Conclusion: These data support the idea that melatonin, which is inexpensive, easy to produce and almost free from serious side effects, might be considered as an adjuvant therapeutic in the treatment of cancer. [ABSTRACT FROM AUTHOR]

Objective: To summarize the role of melatonin in the physiology and pathophysiology of the ovary. Design: Review of literature. Setting: University Health Science Center. Result(s): Melatonin plays an essential role in the pathogenesis of many reproductive processes. Human preovulatory follicular fluid (FF) contains higher concentrations of melatonin than does plasma, and melatonin receptors are present in ovarian granulosa cells (GC). Melatonin has been shown to have direct effects on ovarian function. Reactive oxygen species and apoptosis are involved in a number of reproductive events including folliculogenesis, follicular atresia, ovulation, oocyte maturation, and corpus luteum (CL) formation. Melatonin and its metabolites are powerful antioxidants; the primitive and primary function of melatonin may be its actions as a receptor-independent free radical scavenger and a broad-spectrum antioxidant. A large amount of scientific evidence supports a local role of melatonin in the human reproductive processes. The indole also has potential roles in the pathophysiology of endometriosis, polycystic ovary syndrome (PCOS), and premature ovarian failure (POF). Conclusion(s): We summarize the current understanding of melatonin''s essential functions in the human ovary. Melatonin could become an important medication for improving ovarian function and oocyte quality, and open new opportunities for the management of several ovarian diseases. [Copyright &y& Elsevier]

Hyperbaric oxygen (HBO) is a widely used treatment modality in many diseases. A known side effect of HBO is the production of reactive oxygen species. Many antioxidants such as vitamins C and E, riboflavin and selenium have been used successfully to scavenge the reactive oxygen species caused by HBO administration. In this study, we aimed to see if melatonin, a newly discovered antioxidant, has a protective effect against the overproduction of reactive oxygen species produced by HBO in rat lung tissue. Sixty male Sprague-Dawley rats were divided into 5 groups as follows: control, daytime HBO (3 ATA, 120 min), daytime HBO plus melatonin (10 mg/kg), nighttime HBO and nighttime HBO (under light exposure). The MDA, SOD and CAT levels of daytime and nighttime HBO (under light exposure) increased significantly. This significance was not found in the daytime HBO plus melatonin and nighttime HBO groups when compared with the control. In this study, HBO caused oxidant stress, and melatonin decreased the levels of MDA, SOD and CAT. Moreover, endogenous melatonin was found to be a more effective antioxidant than exogenous 10 mg/kg melatonin. [Copyright &y& Elsevier]

Background: In this study, we aimed to investigate the protective effects of melatonin (MEL) and S-methylisothiourea (SMT) on mechlorethamine (MEC) induced nephrotoxicity. Materials and Methods: A total of 36 male Sprague-Dawley rats were divided into four groups: control, MEC, MEC+MEL, and MEC+SMT. Three groups received single dose of MEC (3.5 mg/kg) via transdermal route. Control animals were given saline only via transdermal route. MEL (100 mg/kg) was administered intraperitoneally 30 min after the application of MEC, and after the same dose of MEL was given every 12 h for a total of six doses. SMT (50 mg/kg) was also given intraperitoneally 30 min after the application of MEC. Results: The tissue TNF-α, IL-1β, and NOx levels were found significantly different for all groups (P < 0.001). MEC application resulted in severe histopathological changes. Melatonin showed meaningful protection against kidney damage. But protection by SMT was weaker. TNF-α and IL-1β levels increased significantly with MEC application, and MEL and SMT ameliorated these increases in kidney tissue. MEC also elevated NOx levels in kidney tissue. Conclusions: Both inflammation and oxidative stress may have an important role in the MEC induced nephrotoxicity. MEL and SMT may also have anti-inflammatory properties, as well as anti-oxidant properties. [ABSTRACT FROM AUTHOR]