Physiological and pharmacological concentrations of melatonin protect against cisplatin-induced acute renal 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.     

Protective effect of melatonin on random pattern skin flap necrosis in pinealectomized rat

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.     

Melatonin protects against myocardial doxorubicin toxicity in rats: role of physiological concentrations

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.     

The protective effect of melatonin on renal ischemia-reperfusion injury in the rat

Oxygen free radicals are considered to be important components involved in the pathophysiological tissue alterations observed during ischemia-reperfusion (I/R). In this study, we investigated the putative protective effects of melatonin treatment on renal I/R injury. Wistar albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 1, 3, 6, 24, 48 hr or 1 wk of reperfusion. Melatonin (10 mg/kg, s.c.) or vehicle was administered twice, 15 min prior to ischemia and immediately before the reperfusion period. At the end of the reperfusion periods, rats were decapitated. Kidney samples were taken for histological examination or the determination of renal malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and protein oxidation (PO). Serum creatinine and blood urea nitrogen (BUN) concentrations were measured for the evaluation of renal function. The results revealed that I/R induced nephrotoxicity, as evidenced by increases in BUN and creatinine levels at each time point, was reversed by melatonin treatment. The decrease in GSH and increases in MDA, MPO and PO induced by I/R indicated that renal injury involves free radical formation. As melatonin administration reversed these oxidant responses, improved renal function and microscopic damage, it seems likely that melatonin protects kidney tissue against oxidative damage.     

Melatonin protects against gentamicin-induced nephrotoxicity in rats

Acute renal failure is a major complication of gentamicin (GEN), which is widely used in the treatment of gram-negative infections. A large body of in vitro and in vivo evidence indicates that reactive oxygen metabolites (or free radicals) are important mediators of gentamicin nephrotoxicity. In this study we investigated the role of free radicals in gentamicin-induced nephrotoxicity and whether melatonin, a potent antioxidant could prevent it. For this purpose female Sprague-Dawley rats were given intraperitoneally either gentamicin sulphate (40 mg/kg), melatonin (10 mg/kg), gentamicin plus melatonin or vehicle (control) twice daily for 14 days. The rats were decapitated on the 15th day and kidneys were removed. Blood urea nitrogen (BUN) and creatinine levels were measured in the blood and malondialdehyde (MDA) and glutathione (GSH) levels, protein oxidation (PO) and myeloperoxidase (MPO) activity were determined in the renal tissue. Gentamicin was observed to cause a severe nephrotoxicity which was evidenced by an elevation of BUN and creatinine levels. The significant decrease in GSH and increases in MDA levels, PO and MPO activity indicated that GEN-induced tissue injury was mediated through oxidative reactions. On the other hand simultaneous melatonin administration protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by GEN treatment.     

Effects of physiological and pharmacological concentrations of melatonin on ischemia–reperfusion arrhythmias in rats: can the incidence of sudden cardiac death be reduced?

Cardiac arrhythmias during ischemia-reperfusion (I/R) are believed to be related to free radicals generated in the heart especially during the period of reperfusion. The pineal secretory product, melatonin, is known to be a potent free radical scavenger and its pharmacological concentrations have been shown to reduce the I/R-induced arrhythmias in isolated rat hearts. However, the physiological role of melatonin in the prevention of these arrhythmias is unknown. Rats were pinealectomized (Px) or sham-operated (non-Px) (control) 2 months before the I/R studies. To produce arrhythmias, left main coronary artery was occluded for 7 min, followed by 7 min reperfusion, in anesthetized rats. The incidence of mortality resulted from irreversible ventricular fibrillation (VF) was found significantly higher in the Px rats (63%) than in the control group (25%). Melatonin administration (0.4 mg/kg, either before ischemia or reperfusion) to Px rats significantly reduced the incidence of total (irreversible plus reversible) and irreversible VF and returned them to control values. On the other hand, melatonin administration (0.4 and 4 mg/kg) to non-Px rats failed to attenuate the I/R arrhythmias, significantly. These results suggest that physiological melatonin concentrations are important to reduce the I/R-induced VF and mortality, while pharmacological concentrations of melatonin did not increase its beneficial effect on these arrhythmias. As melatonin levels have been reported to decrease with age, melatonin replacement therapy may attenuate the incidence of sudden cardiac death especially in older patients.     

Melatonin prevents neutrophil-mediated oxidative injury in Escherichia coli-induced pyelonephritis in rats

Regarding the mechanisms of renal scarring in pyelonephritis, several hypotheses have been put forward, among which oxidative stress is prominent. The present study investigated the possible protective effect of melatonin treatment against Escherichia coli-induced oxidative injury and scarring in renal tissue. For this purpose, 0.1 mL E. coli (ATCC 25922; 10(10) colony-forming units/mL) or saline was injected directly into the renal parenchyma of Wistar rats. Pyelonephritic rats were treated with either saline or melatonin (10 mg/kg) intraperitoneally. Twenty-four hours or 1 wk after E. Coli injection, rats were decapitated and trunk blood samples were collected for BUN, creatinine, tumor necrosis factor-alpha (TNF-alpha) and lactate dehydrogenase (LDH) determination. In kidney samples, histological analysis was performed, and malondialdehyde (MDA), glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen contents were measured. Formation of reactive oxygen species was monitored using a chemiluminescence (CL) technique. Escherichia Coli inoculation caused a significant reduction in renal GSH levels, which was accompanied by significant increases in MDA levels, MPO activity, CL levels and collagen content of the renal tissues (P < 0.05-0.001). Similarly, serum TNF-alpha and, LDH, BUN and creatinine levels were elevated in the pyelonephritic rats when compared with control animals. Melatonin treatment reversed all these biochemical indices, as well as histopathological alterations induced by acute pyelonephritis. The protective effects of melatonin can be ascribed to its ability to inhibit neutrophil infiltration, to balance the oxidant-antioxidant status, and to regulate the generation of inflammatory mediators, suggesting a future role for melatonin in the treatment of acute pyelonephritis.     

贝前列腺素钠对2型糖尿病大鼠肾功能及氧化应激水平的影响

目的 观察贝前列腺素钠(BPS)对2型糖尿病大鼠肾功能及氧化应激水平的影响. 方法 将30只SD大鼠随机分为正常对照组(NC组),2型糖尿病组(T2DM组),BPS治疗组(BPS组),T2DM组和BPS组大鼠给予高脂饮食合并小剂量链脲佐菌素( STZ)腹腔注射,建模成功后,BPS组给予0.6 mg/(kg.d)灌胃,其余饲养条件3组相同,最终纳入实验各组6只.给药8周后检测各组大鼠体质量、血糖、24 h尿量、肾质量体质量比(KW/BW)、24h尿蛋白(24 h Ualb),血肌酐(Cr),尿素氮(BUN)以及各组大鼠氧化应激水平及炎症因子指标,包括总超氧化物歧化酶(SOD)、丙二醛(MDA)、还原型谷胱甘肽(GSH)、白介素6(IL-6)、肿瘤坏死因子(TNF-α)、髓过氧化物酶(MPO)、超敏C反应蛋白(hs-CRP). 结果 给药8周后,T2DM组血糖、尿量、KW/BW、24 h Ualb、Cr、BUN、MIDA、IL-6、TNF-α、MPO、hs-CRP水平均较NC组显著升高;体质量、SOD、GSH水平较NC组显著降低(P＜0.01).BPS组较T2DM组血糖、尿量、KW/BW、24 h Ualb、Cr、IL-6、M DA、TNF-α、MPO、hs-CRP水平显著降低(P＜0.05或0.01),体质量、SOD、GSH水平显著升高(P＜0.05). 结论 BPS可通过降低氧化应激水平,减少炎症因子的生成,显著减少糖尿病肾病大鼠尿蛋白排泄量,改善其肾功能,对T2DM大鼠肾脏具有保护作用.     

Melatonin protects against endosulfan-induced oxidative tissue damage in rats

Abstract:  Endosulfan is a chlorinated cyclodiene insecticide which induces oxidative stress. In this study, we investigated the possible protective effect of melatonin, an antioxidant agent, against endosulfan (Endo)-induced toxicity in rats. Wistar albino rats (n = 8) were administered endosulfan (22 mg/kg/day orally) followed by either saline (Endo group) or melatonin (10 mg/kg/day, Endo + Mel group) for 5 days. In other rats, saline (control group) or melatonin (10 mg/kg/day, Mel group) was injected for 5 days, following corn oil administration (vehicle of endosulfan). Measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were performed in liver and kidney. Furthermore, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine levels, lactate dehydrogenase (LDH) activity were measured in the serum samples, while tumor necrosis factor-α (TNF-α), interleukin-β (IL-β) and total antioxidant capacity (AOC) were assayed in plasma samples. Endosulfan administration caused a significant decrease in tissue GSH and plasma AOC, which was accompanied with significant rises in tissue MDA and collagen levels and MPO activity. Moreover, the proinflammatory mediators (TNF-α and IL-β), LDH activity, AST, ALT, creatinine and BUN levels were significantly elevated in the endosulfan-treated rats. On the other hand, melatonin treatment reversed all these biochemical alterations induced by endosulfan. Our results suggest that oxidative mechanisms play an important role in endosulfan-induced tissue damage and melatonin, by inhibiting neutrophil infiltration, balancing oxidant–antioxidant status and regulating the generation of inflammatory mediators, ameliorates oxidative organ injury as a result of endosulfan toxicity.     

Melatonin ameliorates chronic renal failure-induced oxidative organ damage in rats

Chronic renal failure (CRF) is associated with oxidative stress that promotes production of reactive oxygen species (ROS). Melatonin, the chief secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. The aim of this study was to examine the role of melatonin in protecting the aorta, heart, corpus cavernosum, lung, diaphragm, and kidney tissues against oxidative damage in a rat model of CRF, which was induced by five of six nephrectomy. Male Wistar albino rats were randomly assigned to either the CRF group or the sham-operated control group, which had received saline or melatonin (10 mg/kg, i.p.) for 4 wk. CRF was evaluated by serum blood urea nitrogen (BUN) level and creatinine measurements. Aorta and corporeal tissues were used for contractility studies, or stored along with heart, lung, diaphragm, and kidney tissues for the measurement of malondialdehyde (MDA, an index of lipid peroxidation), protein carbonylation (PC, an index for protein oxidation), and glutathione (GSH) levels (a key antioxidant). Plasma MDA, PC, and GSH levels and erythrocytic superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in CRF. In the CRF group, the contraction and the relaxation of aorta and corpus cavernosum samples decreased significantly compared with controls (P < 0.05-0.001). Melatonin treatment of the CRF group restored these responses. In the CRF group, there were significant increases in tissue MDA and PC levels in all tissues with marked reductions in GSH levels compared with controls (P < 0.05-0.001). In the plasma, while MDA and PC levels increased, GSH, SOD, CAT, and GSH-Px activities were reduced. Melatonin treatment reversed these effects as well. In this study, the increase in MDA and PC levels and the concomitant decrease in GSH levels of tissues and plasma and also SOD, CAT, GSH-Px activities of plasma demonstrate the role of oxidative mechanisms in CRF-induced tissue damage, and melatonin, via its free radical scavenging and antioxidant properties, ameliorates oxidative organ injury. CRF-induced dysfunction of the aorta and corpus cavernosum of rats was reversed by melatonin treatment. Thus, supplementing CRF patients with adjuvant therapy of melatonin may have some benefit.     

肾毒清冲剂对慢性肾功能不全大鼠模型的治疗作用

用0.75％腺漂呤饲料喂养Wistar大鼠10周制成肾功能不全模型,以肾毒清冲剂1.25g/kg（组）、2.5g/kg（组）、5g/kg（组）分别灌胃,并设包醛氧化淀粉组（1.3g/kg）、模型对照组和正常对照组。大鼠喂养28天后测血清中SOD、GSH－Px活力、MDA含是量及BUN、Cr、钙、磷、TG、TCh、TP、AL值;计算脾、胸腺指数;做肾脏病理检查。结果发现：肾毒清冲剂能显著提高慢性肾功能不全大鼠中SOD、GSH－Px活力,降低MDA含量,提高胸腺指数,降低血清中BUN、Cr的含量,升高钙含量,减轻肾组织损伤。     

Melatonin, a pineal secretory product with antioxidant properties, protects against cisplatin-induced nephrotoxicity in rats

In an attempt to define the role of the pineal secretory melatonin and an analogue, 6-hydroxymelatonin (6-OHM), in limiting oxidative stress, the present study investigated the cisplatin (CP)-induced alteration in the renal antioxidant system and nephroprotection with the two indolamines. Melatonin (5 mg/kg), 6-OHM (5 mg/kg), or an equal volume of saline were administered intraperitoneally (i.p.) to male Sprague Dawley rats 30 min prior to an i.p. injection of CP (7 mg/kg). After CP treatment, the animals each received indolamine or saline every day and were sacrificed 3 or 5 days later and plasma as well as kidney were collected. Both plasma creatinine and blood urea nitrogen increased significantly following CP administration alone; these values decreased significantly with melatonin co-treatment of CP-treated rats. In the kidney, CP decreased the levels of GSH (reduced glutathione)/GSSG (oxidized glutathione) ratio, an index directly related to oxidative stress. When animals were treated with melatonin, the reduction in the GSH/GSSG ratio was prevented. Treatment of CP-enhanced lipid peroxidation in the kidney was again prevented in animals treated with melatonin. The activity of the antioxidant enzyme, glutathione peroxidase (GSH-Px), decreased as a result of CP administration, which was restored to control levels with melatonin co-treatment. Upon histological analysis, damage to the proximal tubular cells was seen in the kidneys of CP-treated rats; these changes were prevented by melatonin treatment. 6-OHM has been shown to have some antioxidative capacity, however, the protective effects of 6-OHM against CP-induced nephrotoxicity were less than those of melatonin. The residual platinum concentration in the kidney of melatonin co-treated rats was significantly lower than that of rats treated with CP alone. It is concluded that administration of CP imposes a severe oxidative stress to renal tissue and melatonin confers protection against the oxidative damage associated with CP. This mechanism may be reasonably attributed to its radical scavenging activity, to its GSH-Px activating property, and/or to its regulatory activity for renal function.     

Melatonin reduces uranium-induced nephrotoxicity in rats

The protective role of exogenous melatonin on U-induced nephrotoxicity was investigated in rats. Animals were given single doses of uranyl acetate dihydrate (UAD) at 5 mg/kg (subcutaneous), melatonin at 10 or 20 mg/kg (intraperitoneal), and UAD (5 mg/kg) plus melatonin (10 or 20 mg/kg), or vehicle (control group). In comparison with the UAD-treated group only, significant beneficial changes were noted in some urinary and serum parameters of rats concurrently exposed to UAD and melatonin. The increase of U excretion after UAD administration was accompanied by a significant reduction in the renal content of U when melatonin was given at a dose of 20 mg/kg. Melatonin also reduced the severity of the U-induced histological alterations in kidney. In renal tissue, the activity of the superoxide dismutase (SOD) and the thiobarbituric acid reactive substances (TBARS) levels increased significantly as a result of UAD exposure. Following UAD administration, oxidative stress markers in erythrocytes showed a reduction in SOD activity and an increase in TBARS levels, which were significantly restored by melatonin administration. In plasma, reduced glutathione (GSH) and its oxidized form (GSSG) were also altered in UAD-exposed rats. However, only the GSSG/GSH ratio was restored to control levels after melatonin treatment. Oxidative damage was observed in kidneys. Melatonin administration partially restored these adverse effects. It is concluded that melatonin offers some benefit as a potential agent to treat acute U-induced nephrotoxicity.     

Melatonin protects against ionizing radiation-induced oxidative damage in corpus cavernosum and urinary bladder in rats

The objective of this study was to examine the potential radioprotective properties of pharmacological doses of melatonin on corpus cavernosum and bladder tissues of whole-body irradiated (IR) rats. A total of 32 male Sprague-Dawley rats were exposed to irradiation performed with a LINAC which produced 6 MV photons at a focus 100 cm distant from the skin. Under ketamine anesthesia, 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 and 10 mg/kg, i.p.) and decapitated at 12 hr after exposure to irradiation. Another group of rats was followed for 72 hr after IR, where melatonin injections were repeated once daily. Tissue levels of malondialdehyde (MDA), an index of lipid peroxidation, and glutathione (GSH), a key antioxidant, were estimated in corpus cavernosum and urinary bladder. Tissues were also examined microscopically. The results demonstrate that both 12 and 72 hr following IR, tissue levels of MDA were elevated (P < 0.001), while GSH levels were reduced (P < 0.01) in both tissues. On the other hand, melatonin reversed these changes significantly (P < 0.05-0.01), concomitant with the improvement in histological appearances. Our results show that whole-body irradiation causes oxidative damage in the tissues of the genitourinary system. As melatonin administration reversed oxidative organ injury, as assessed by biochemical and histopathological findings, it is suggested that supplementing cancer patients with adjuvant therapy of melatonin may have some benefit for successful radiotherapy.     

Protective effects of melatonin,vitamin E and N-acetylcysteine against acetaminophen toxicity in mice: a comparative study

Acetaminophen (AA) is a commonly used analgesic and antipyretic drug; however, when used in high doses, it causes fulminant hepatic necrosis and nephrotoxic effects in both humans and experimental animals. It has been reported that the toxic effects of AA are the result of oxidative reactions that take place during its metabolism. In this study we investigated if melatonin, vitamin E or N-acetylcysteine (NAC) are protective against AA toxicity in mice. The doses of the antioxidants used were as follows: melatonin (10 mg/kg), vitamin E (30 mg/kg) and NAC (150 mg/kg). Blood urea nitrogen (BUN), serum creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels in blood, and glutathione (GSH), malondialdehyde (MDA), oxidized protein levels and myeloperoxidase (MPO) activity in liver and kidney tissues were measured. BUN and serum creatinine, ALT and AST levels which were increased significantly following AA treatment decreased significantly after pretreatment with either vitamin E, melatonin or NAC; however, they were not reduced to control levels. ALT and AST levels were significantly higher at 4 hr compared with the 24 hr levels after AA administration. However, BUN and creatinine levels were significantly elevated only at 24 hr. GSH levels were reduced while MDA, MPO and oxidized protein levels were increased significantly following AA administration. These changes were reversed by pretreatment with either melatonin, vitamin E or NAC. Liver toxicity was higher at 4 hr, whereas nephrotoxicity appeared to be more severe 24 hr after treatment with AA. Vitamin E was the least efficient agent in reversing AA toxicity while melatonin, considering it was given as at lower dose than either vitamin E or NAC, was the most effective. This may be the result of the higher efficacy of melatonin in scavenging various free radicals and also because of its ability in stimulating the antioxidant enzymes.     

The Effect of Melatonin on TNBS-Induced Colitis

Ulcerative colitis is a multifactorial inflammatory disease of the colon and rectum with an unknown etiology. The present study was undertaken to investigate the effect of melatonin administration on oxidative damage and apoptosis in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Rats were divided into four groups as follows: Group 1 (n=8)—TNBS colitis; Group 2 (n=8)—melatonin, 10 mg/kg/day ip, for 15 days in addition to TNBS; Group 3 (n=8)—melatonin alone, 10 mg/kg/day ip, for 15 days; and Group 4 (n=8)—isotonic saline solution, 1ml/rat ip, for 15 days (sham control group). Colonic myeloperoxidase (MPO) activities, malondialdehyde (MDA) levels, and glutathione (GSH) levels are indicators of oxidative damage, while caspase-3 activities reveal the degree of apoptosis of the colonic tissue. In all TNBS-treated rats, colonic MPO activity and MDA levels were found to be increased significantly compared to those in the sham group. Colonic MPO activity and MDA levels were significantly lower in the melatonin treatment group compared to TNBS-treated rats. GSH levels of colonic tissues were found to be significantly lower in TNBS-treated rats compared to the sham group. Treatment with melatonin significantly increased GSH levels compared to those in TNBS-treated rats. Caspas-3 activity of colonic tissues was found to be significantly higher in TNBS-treated rats compared to the sham group. Treatment with melatonin significantly decreased caspase-3 activity compared to that in TNBS-treated rats. These results imply a reduction in mucosal damage due to anti-inflammatory and anti-apoptotic effects of melatonin.     

Cataractogenesis and lipid peroxidation in newborn rats treated with buthionine sulfoximine: Preventive actions of melatonin

ABSTRACT: The purpose of this study was to examine the influence of exogenously administered melatonin on cataract formation and lipid peroxidation in newborn rats treated with buthionine sulfoximine (BSO), a drug which inhibits the rate-limiting enzyme in glutathione (GSH) synthesis, y-glutamylcysteine synthase, thereby depleting animals of their stores of the important intracellular antioxidant, GSH. BSO (3 mmol/kg BW) was given for three consecutive days beginning on postnatal day 2; melatonin (4 mg/kg) was injected daily beginning on postnatal day 2 and continuing until the animals were killed (either day 9 or day 17 after birth). None of the control animals (rats treated with neither BSO nor with melatonin) developed lenticular opacification during the observation period. In the BSO-treated rats, 16 of 18 animals (89%) had observable cataracts when they were examined. In rats that received both BSO and melatonin, the incidence of cataracts was highly significantly decreased, i.e., only 3 of 18 rats (7%) had observable cataracts. In addition to cataracts, the level of lipid peroxidation products (malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)) was examined in the lens, brain, liver, lung, and kidney of control and experimental animals. In BSO-treated rats, the lens, kidney, and lung exhibited increased levels of MDA plus 4-HDA relative to those measured in the control rats; these increases were reversed in the BSO-treated rats who were injected with melatonin daily. While BSO administration did not increase basal levels of MDA plus 4-HDA in either the brain or liver, melatonin reduced levels of lipid peroxidation products below those measured in the control rats (at 17 days after birth). The changes induced by melatonin are consistent with the free-radical scavenging and antioxidative properties of this indole.     

Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats

Regarding the mechanisms of methotrexate (MTX) hepatotoxicity and nephrotoxicity, several hypotheses have been put forward, among which oxidative stress (including depletion of glutathione) is likely. This investigation elucidates the role of free radicals in MTX-induced toxicity and the protection by melatonin. Wistar albino rats were injected with MTX intraperitoneally. Following a single dose of MTX (20 mg/kg), either saline (MTX group) or melatonin (10 mg/kg, MTX + Mel group) was administered for 5 days. In other rats, physiologic saline (control group) or melatonin (10 mg/kg, Mel group) was injected for 5 days, following a single injection of saline. On the sixth day, rats were killed to obtain blood, liver, and kidney tissue samples. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH), a key antioxidant, levels were evaluated in blood and tissue homogenates. Reactive oxygen metabolite-induced inflammatory changes in kidney and liver tissues were evaluated by measuring myeloperoxidase (MPO) activity, an index of neutrophil infiltration. MTX administration resulted in increased MDA levels and MPO activity and decreased GSH levels in the blood, liver, and kidney whereas melatonin reversed these effects. When melatonin was administered alone, no significant changes in biochemical parameters were noted. In conclusion, the present study suggests that melatonin may be of therapeutic benefit when used with MTX.     

重组人促红素对老年慢性肾衰病人氧自由基及抗氧化酶活性的影响

目的　探讨重组人促红素（ｒ Ｈ  Ｅ Ｐ Ｏ ）对慢性肾衰患者体内氧自由基及抗氧化酶活性的影响。方法　测定 １９ 例老年慢性肾衰尿毒症期患者 ｒ Ｈ  Ｅ Ｐ Ｏ 治疗前后血浆 Ｍ Ｄ Ａ 、 Ｓ Ｏ Ｄ 及红细胞 Ｇ Ｓ Ｈ  Ｐｘ 含量。结果　ｒ Ｈ  Ｅ Ｐ Ｏ 治疗后慢性肾衰病人 Ｍ Ｄ Ａ 含量降低, Ｓ Ｏ Ｄ 、 Ｇ Ｓ Ｈ  Ｐｘ 活性升高。结论　ｒ Ｈ  Ｅ Ｐ Ｏ 纠正肾性贫血同时,可清除体内氧自由基,提高抗氧化酶活性。     

Role of exogenous melatonin in reducing the nephrotoxic effect of daunorubicin and doxorubicin in the rat

The aim of these studies was to examine the nephroprotective effect of melatonin following the anthracycline administration [daunorubicin (DNR); doxorubicin (DOX)] in rats. Application of these drugs in chemotherapy is limited because of their cardiotoxicity and nephrotoxicity. Rats of the Buffalo strain were divided into groups according to the cytostatic drug used, its dose and sequence of administration [DNR or DOX single (i.v.) dose of 10 mg/kg b.w., i.e. acute intoxication and 3 mg/kg b.w. (i.v.) weekly for 3 wk, subchronic intoxication]. Melatonin was administered subcutaneously before and after every injection of a cytostatic drug at a dose of 10 mg/kg b.w. The severity of renal alterations was examined both biochemically [levels of lipid peroxidation markers, malonyldialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)], or histologically. A statistically significant decrease in renal damage was noted after melatonin administration to acutely or subchronically intoxicated DNR-treated and DOX-treated rats. Biochemical assays revealed significant decreases in MDA and 4-HDA levels following application of melatonin during subchronic DNR or DOX intoxication. In summary, melatonin was found to exert a protective effect on the kidney, which was particularly evident after subchronic DOX and DNR intoxication, using both histological or biochemical methods.