Amikacin-induced acute renal injury in rats: protective role of melatonin

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

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.     

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 ischemia-reperfusion injury in the groin (inferior epigastric) flap model in rats

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

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.     

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 provides neuroprotection by reducing oxidative stress and HSP70 expression during chronic cerebral hypoperfusion in ovariectomized rats

Abstract:  Oxidative stress is believed to contribute to functional and histopathologic disturbances associated with chronic cerebral hypoperfusion (CCH) in rats. Melatonin has protective effects against cerebral ischemia/reperfusion injury. This effect has mainly been attributed to its antioxidant properties. In the present study, we evaluate the effects of melatonin on chronic cerebral hypoperfused rats and examined its possible influence on oxidative stress, superoxide dismutase (SOD) activity, reduced glutathione (GSH) levels, and heat shock protein (HSP) 70 induction. CCH was induced by permanent bilateral common carotid artery occlusion in ovariectomized female rats. Extensive neuronal loss in the hippocampus at day 14 following CCH was observed. The ischemic changes were preceded by increases in malondialdehyde (MDA) concentration and HSP70 induction as well as reductions in GSH and SOD. Melatonin treatment restored the levels of MDA, SOD, GSH, and HSP70 induction as compared to the ischemic group. Histopathologic analysis confirmed the protective effect of melatonin against CCH-induced morphologic alterations. Taken together, our results document that melatonin provides neuroprotective effects in CCH by attenuating oxidative stress and stress protein expression in neurons. This suggests melatonin may be helpful for the treatment of vascular dementia and cerebrovascular insufficiency.     

Oxidative stress and lipid peroxidation products:effect of pinealectomy or exogenous melatonin injections on biomarkers of tissue damage during acute pancreatitis

BACKGROUND:Melatonin (N-acetyl-5-methoxytripta-mine) is a free radical scavenger and a strong antioxidant,secreted by the pineal gland.In this study,we evaluated the effects of decreasing and increasing serum melatonin levels on malonyldialdehyde (MDA),superoxide dismutase (SOD),and reduced glutathione (GSH) levels in pancreatic tissue from rats with experimental acute pancreatitis.METHODS:Experimental acute pancreatitis was induced in three groups of Wistar albino rats (10 animals per group) by pancreatic ...     

Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in rats

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized condition that may progress to end-stage liver disease, which ranges from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Oxidative stress and lipid peroxidation are key pathophysiological mechanisms in NAFLD. We investigate the preventive effects of intraperitoneal administration of melatonin (2.5, 5, 10 mg/kg, daily, respectively) in NAFLD rats induced by high-fat diets for 12 wk. Liver damage was evaluated by serological analysis, serum and hepatic lipid assay as well as hematoxylin-eosin staining in liver sections. Oxidative stress and lipid peroxidation were assessed by measuring malondialdehyde (MDA) levels and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in liver. The results showed that high-fat diet induced oxidative stress with extensive liver steatosis in rats. Melatonin (5 or 10 mg/kg) was effective in reducing hepatic steatosis and inflammation with lowering serum alanine aminotransferase, aspartate aminotransferase, and levels liver total cholesterol and triglycerides in high-fat diet rats. Moreover, melatonin (2.5, 5, 10 mg/kg) increased SOD and GSH-Px activities and the 10 mg/kg dose of melatonin reduced MDA levels in liver. This study shows that melatonin exerts protective effects against fatty liver in rats induced by high-fat diet possibly through its antioxidant actions.     

Ultrastructural clues for the protective effect of melatonin against oxidative damage in cerulein-induced pancreatitis

The role of oxidative stress has been evaluated in experimental models of acute pancreatitis (AP). The aim of this study is to investigate the effect of melatonin on the ultrastructural changes in cerulein-induced AP in rats. Acute pancreatitis was induced by two i.p. injections of cerulein at 2-hr intervals (50 microg/kg BW). One group received additionally melatonin (20 mg/kg BW) i.p. before each injection of cerulein. The rats were sacrificed 12 hr after the last injection. Pancreatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides and changes in the antioxidant enzyme levels, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total glutathione (GSH) levels. Ultrastructural examination was performed using a transmission electron microscope. Formation of numerous, large autophagosomes, mitochondrial damage, dilatation of rough endoplasmic reticulum (RER) and Golgi apparatus, margination and clumping of nuclear chromatin were the major ultrastructural alterations observed in the AP group. Melatonin administration prevented mitochondrial and nuclear changes and dilatation of RER and Golgi apparatus. Rare, small autophagosomes were present within the cytoplasm of some of the acinar cells. Pancreatic damage was accompanied by a significant increase in tissue MDA levels (P < 0.05) and a significant decrease in CAT, SOD, GPx activities and GSH levels (P < 0.005). Melatonin administration significantly reduced MDA levels but increased CAT, SOD, GPx activities and GSH levels (P < 0.005). Melatonin also reduced serum amylase and lipase activities, which were significantly elevated in AP (P < 0.05 and P < 0.005 respectively). These results suggest that oxidative injury is important in the pathogenesis of AP. Melatonin is potentially capable of limiting pancreatic damage produced during AP by protecting the fine structure of acinar cells and tissue antioxidant enzyme activities.     

Melatonin inhibits lipid peroxidation and stimulates the antioxidant status of diabetic rats

Although melatonin has been established as a free radical scavenger and antioxidant, its effects in diabetes have not been thoroughly investigated. The purpose of this study, therefore, was to investigate the effects of melatonin administration on lipid peroxidation and antioxidant status in streptozotocin (STZ)-induced diabetes in rats. Concentrations of malondialdehyde (MDA) and reduced glutathione (GSH) in erythrocytes and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were compared in 3 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 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 i.p. dose of melatonin per day. After 6 wk, the rats in groups II and III had significantly lower body weights and significantly higher blood glucose levels than the rats of group I (P<0.001 and P<0.001, respectively). There were no significant differences in body weight or blood glucose levels between groups II and III. MDA levels in untreated diabetic rats were higher than those in control group rats and in diabetic rats treated with melatonin (P<0.01 and P<0.05, respectively). However, MDA levels in diabetic rats treated with melatonin were not different from those of the control group. The GSH, GSH-Px and SOD levels of untreated diabetic rats were significantly lower than those of the control group (P<0.02, P<0.002 and P<0.05, respectively). In group III, however, melatonin prevented decreases in the thiol antioxidant and the associated enzymes, and so these levels were not significantly different from those in the control group. These results confirm the presence of oxidative stress in STZ-induced experimental diabetes and indicate the beneficial free radical-scavenging and antioxidant properties of melatonin.     

Antioxidative effects of melatonin administration in elderly primary essential hypertension patients

The imbalance of the redox state of the aging organism may be involved in the development of primary essential hypertension. Melatonin, a potent antioxidant agent, was found to exert a hypotensive effect and improve the function of the cardiovascular system. The aim of this study was to determine the influence of melatonin supplementation on oxidative stress parameters in elderly primary essential hypertensive (EH) patients, controlled by a diuretic (indapamide) monotherapy. The levels of malondialdehyde (MDA) and reduced glutathione (GSH), activities of Cu-Zn superoxide dismutase (SOD-1), catalase (CAT) and glutathione peroxidase (GSH-Px) in erythrocytes, the plasma level of nitrate/nitrite, the content of carbonyl groups of plasma proteins and morning melatonin levels in the serum of 17 elderly EH patients were determined at the baseline and after the 15th and 30th days of melatonin supplementation (5 mg daily). Melatonin administration resulted in a significant increase in the morning melatonin concentration, SOD-1 and CAT activities, and a reduction in the MDA level. Statistically significant alterations in the levels of GSH, nitrate/nitrite and carbonyl groups and the activity of GSH-Px were not observed. These results indicate an improvement in the antioxidative defense of the organism by melatonin supplementation in the examined group and may suggest melatonin supplementation as an additional treatment supporting hypotensive therapy in elderly EH patients.     

Inhibitory effect of melatonin on lung oxidative stress induced by respiratory syncytial virus infection in mice

Abstract: Previous research has shown that antioxidant (butylated hydroxyanisole) treatment ameliorates respiratory syncytial virus (RSV)‐induced disease and lung inflammation. Melatonin has been reported to exhibit a wide varieties of biological effects, including antioxidant and anti‐inflammation, and has no evident toxicity and side effect. But it is not known whether melatonin would modify RSV‐induced lung disease and oxidative stress. The present study was to establish the involvement of oxidative stress in the pathogenesis of RSV‐induced lung inflammation, and to investigate the protective effect of administration of melatonin in mice with RSV‐induced oxidative pulmonary injury for 4 days. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH) and superoxide dismutase (SOD) and nitric oxide (NO) levels were evaluated in lung tissue homogenates by spectrophotometry. Hydroxyl radical (˙OH), one of the indicators of free radical formation, was also detected in lung homogenates by Fenton reaction. Tumor necrosis factor‐a (TNF‐a) concentrations in mouse serum were measured with ELISA assay. The results demonstrated that the mice intranasally inoculated with RSV resulted in oxidative stress changes by increasing NO, MDA and ˙OH levels, and decreasing GSH and SOD activities, whereas administration of melatonin significantly reversed all these effects. Furthermore, melatonin inhibited production of proinflammatory cytokines such as TNF‐a in serum of RSV‐infected mice. These results suggest that melatonin ameliorates RSV‐induced lung inflammatory injury in mice via inhibition of oxidative stress and proinflammatory cytokine production and may be as a novel therapeutic agent in virus‐induced pulmonary infection.     

Melatonin reduces dimethylnitrosamine-induced liver fibrosis in rats

Increased deposition of the extracellular matrix components, particularly collagen, is a central phenomenon in liver fibrosis. Stellate cells, the central mediators in the pathogenesis of fibrosis are activated by free radicals, and synthesize collagen. Melatonin is a potent physiological scavenger of hydroxyl radicals. Melatonin has also been shown to be involved in the inhibitory regulation of collagen content in tissues. At present, no effective treatment of liver fibrosis is available for clinical use. We aimed to test the effects of melatonin on dimethylnitrosamine (DMN)-induced liver damage in rats. Wistar albino rats were injected with DMN intraperitoneally. Following a single dose of 40 mg/kg DMN, either saline (DMN) or 100 mg/kg daily melatonin was administered for 14 days. In other rats, physiologic saline or melatonin were injected for 14 days, following a single injection of saline as control. Hepatic fibrotic changes were evaluated biochemically by measuring tissue hydroxyproline levels and histopathogical examination. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH) and superoxide dismutase (SOD) levels were evaluated in blood and tissue homogenates. DMN caused hepatic fibrotic changes, whereas melatonin suppressed these changes in five of 14 rats (P < 0.05). DMN administration resulted in increased hydroxyproline and MDA levels, and decreased GSH and SOD levels, 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 functions as a potent fibrosuppressant and antioxidant, and may be a therapeutic choice.     

人参果粗多糖的抗衰老作用研究

目的　观察人参果粗多糖（ＣＰＦＧ）的抗衰老作用。方法　ＣＰＦＧ按２００、４００ ｍ ｇ／ｋｇ 给老年大鼠连续灌胃３０ ｄ,测血清ＭＤＡ含量,脑和肝组织脂褐质（Ｌｆ）含量,皮肤和肝组织羟脯氨酸（Ｈｙｐ）含量及血清ＳＯＤ、ＣＡＴ、ＧＳＨ－Ｐｘ 活性。结果　ＣＰＦＧ 两剂量组均能明显降低老年大鼠血清ＭＤＡ 含量及脑和肝组织Ｌｆ含量,明显提高血清ＳＯＤ、ＣＡＴ、ＧＳＨ－Ｐｘ 活性及皮肤Ｈｙｐ 含量。结论　ＣＰＦＧ可能通过改善自由基代谢发挥抗衰老作用。     

Preventive effect of melatonin on bleomycin-induced lung fibrosis in rats

Oxidative stress has an important role in the pathogenesis of idiopathic pulmonary fibrosis. Melatonin has direct and indirect free radical-detoxifying activity. The present study investigated whether melatonin treatment attenuates bleomycin-induced lung fibrosis in rats. A group of rats was given one dose of bleomycin while the control animals were given saline. The first dose of melatonin (4 mg/kg/day) was given 2 days before the bleomycin injection. At day 14, fibrotic changes were evaluated using Aschoft's criteria and lung hydroxyproline content. Bleomycin produced a 2.7-fold rise in the fibrosis score that was decreased 65% by melatonin (P < 0.05) and a 1.4-fold increase in hydroxyproline content which was completely prevented by melatonin. Protein carbonyl and thiobarbituric acid reactive substances levels, which were significantly elevated in the bleomycin treated rats, were significantly attenuated by melatonin. Bleomycin administration significantly reduced the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissue. The reduction in CAT activity was prevented by melatonin but SOD and GSH-Px were not influenced. These results revealed that melatonin may prevent the development of bleomycin-induced lung fibrosis via the repression of protein and lipid peroxidation.     

褪黑素对糖尿病患者氧化应激抑制作用和糖脂代谢影响的观察

目的 探讨褪黑素对糖尿病患者氧化应激的抑制作用及糖脂代谢的影响。 方法 1998-12～2003-04东南大学附属中大医院采用随机、单盲、安慰剂平行对照的方法,观察褪黑素及安慰剂对91例糖尿病患者血清丙二醛(MDA)及超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)的影响,并分析上述影响与糖脂代谢变化之间的关系。 结果 治疗前糖尿病患者血清SOD、GSH-Px水平下降,MDA水平上升。褪黑素组8周处理后血清SOD和GSH-Px水平上升,而MDA水平明显下降,与处理前相比差异有显著;安慰剂组处理前后患者血清SOD、GSH-Px及MDA水平无明显变化。褪     

The role of melatonin on gastric mucosal cell proliferation and telomerase activity in ageing

Abstract:  Despite antiproliferative effects of melatonin on cultured tumor cells, its effects on normal cells are less clear. The action of melatonin on telomerase activity in ageing of gastric mucosal tissues also is not known. In this study, we investigated the age-related changes in telomerase activity and cellular proliferation rate of gastric mucosa and the effect of melatonin. A total of 37 young (4 months old), and aged (20 months old) Wistar rats, kept under equal periods of light and dark, were divided into control [(PBS), i.p. for 21 days] and melatonin-treated (10 mg/kg melatonin, i.p. for 21 days) groups. Telomerase activity, cell proliferation rate, malondialdehyde (MDA) and glutathione (GSH) levels of the stomach were determined. Melatonin significantly inhibited the gastric mucosal proliferation rate of both young and aged rats. Telomerase activity was significantly reduced in aged rats compared to young animals. Melatonin significantly increased the telomerase activity of both young and aged rats. The MDA levels of gastric mucosa in the aged rats were significantly higher than those of the younger rats. On the contrary, the GSH levels of gastric mucosa of the aged group were significantly lower than that of the young rats. While melatonin had no effect on GSH levels of either young or aged rats, it significantly decreased the MDA levels in aged animals. In conclusion, melatonin may delay the ageing of gastric mucosa by inhibiting the replicative cellular senescence via its stimulatory effect on telomerase activity and suppressive effect on cellular proliferation and lipid peroxidation.     

D-半乳糖催老大鼠氧化水平和抗氧化能力的变化

目的　研究人工催老大鼠氧化水平和抗氧化能力的改变。方法　采用D 半乳糖 6 0mg/kg皮下注射 4 2d ,复制人工催老大鼠模型 ,以观察催老大鼠血中丙二醛 (MDA)、一氧化氮 (NO)的含量、超氧化物歧化酶 (SOD)、谷胱甘肽过氧化物酶 (GSH Px)、一氧化氮合酶 (NOS)和脑单胺氧化酶 (MAO)等活性的变化。结果　催老大鼠与正常大鼠相比 ,血清中MDA含量增高 ,SOD和GSH Px活性降低 ,脑MAO活性增高 ,NO含量和NOS活性无明显改变。结论　D 半乳糖可以使催老大鼠氧化水平增加 ,抗氧化能力下降 ;且两者变化无性别差异。     

Protective effect of low dose of melatonin against cholestatic oxidative stress after common bile duct ligation in rats

AIM: To investigate the role of oxidative injury and the effect of exogenous melatonin administration on liver damage induced by bile duct ligation (BDL), and second, to evaluate the role of nitric oxide (NO), a free oxygen radical, in oxidative injury. METHODS: Thirty-two Sprague-Dawley rats were assigned to four groups: sham operation (SO), BDL, BDL+melatonin, and BDL+vehicle. Cholestasis was achieved by double ligature of the common bile duct. Melatonin was injected intraperitoneally 500 μg/(kg·d) for 8 d. Hepatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides, measured as malondialdehyde (MDA), and reduced GSH. Total nitrite (NOx) concentrations were determined in hepatic homogenates. Histopathological examination was performed using a histological scoring system. RESULTS: The histopathological changes including portal inflammation, necrosis,apoptosis, focal inflammation and fibrosis were severe in the BDL and BDL+vehicle groups. There were numerous large areas of coagulation necrosis. Histological Activity Index scores of these groups were significantly higher than that of the SO group. Treatment with melatonin reduced these alterations significantly. The degree of necro-inflammation and fibrosis showed significant difference between the BDL and BDL+melatonin groups. BDL was accompanied by a significant increase in MDA and NOx, and a significant decrease in GSH levels. Mean±SE values of MDA, GSH and NOx levels of SO group were 147.47±6.69, 0.88±0.33 μmol/g and 180.70±6.58 nm/g, respectively. The values of BDL group were 200.14±21.30, 0.65±0.02 μmol/g, and 400.46±48.89 nm/g, respectively, whereas the values of BDL+melatonin group were 115.93±6.8,0.74±0.02 μmol/g, and 290.38±32.32 nm/g, respectively. Melatonin treatment was associated with a significant recovery of MDA, GSH and NOx levels. CONCLUSION: We have concluded that oxidative stress is associated with the pathogenesis of cholestatic liver damage and NO contributes to oxidative damage. Melatonin, even at low dose, is an efficient agent in reducing negative parameters of cholestasis.