Protective role of melatonin and retinol palmitate in oxidative stress and hyperlipidemic nephropathy induced by adriamycin in rats

Abstract: We have studied the effects of melatonin and retinol palmitate (RP) on the nephropathy and oxidative stress induced by a single and high dose of adriamycin (AD) in Wistar male rats. A dose of melatonin (75 μg/ kg/day) and a dose of RP (0.25 g oily solution/kg/day, sc) were injected 3 and 9 days before and after the administration of AD (25 mg/kg, i.p.), respectively. After the decapitation, samples were taken from the neck vascular trunk in order to determine the triglycerides, total cholesterol, phospholipids, HDL-cholesterol, total proteins, urea, lipoperoxides, and reduced glutathione (GSH). We estimated the lipoperoxide and glutathione (GSH) contents in renal homogenates, and the excretion of proteins in urine over a 24 hr period. The administration of AD caused significant increases in proteinuria and in the other parameters studied [lipids (triglycerides, total cholesterol, phospholipids, and HDL-cholesterol), nonprotein nitrogen compounds, and lipoperoxides]. AD increased the lipoperoxide content, but it decreased the GSH content in the kidney. Both melatonin and RP, although melatonin more significantly, decreased the intensity of the changes produced by the administration of AD alone. In fact, melatonin was quite efficient in reducing the formation of lipoperoxides, restoring renal GSH content and decreasing remarkably the severity of proteinuria. These results support the powerful antioxidant action of melatonin at renal level and a lower antioxidant action of retinol. Likewise, these data reinforce the hypothesis which supports the pathogenetic role and the close relation between the oxidative stress and the expression of the nephropathy induced by AD. However, in spite of this obvious antioxidant effect of melatonin in the kidney, additional studies are required to establish accurately the role of this pineal indole in the regulation and dynamics of the antioxidative defense enzyme system, which neutralizes the damaging effect of free radicals, both endogenous and exogenous, in this organ.     

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.     

Protective effects of chronic melatonin treatment against renal injury in streptozotocin-induced diabetic rats

The aim of this study was to investigate the effects of melatonin as an antioxidant, on prevention and treatment of streptozotocin (STZ)-induced diabetic renal injury in rats. Male Wistar rats were divided into four groups: (1) untreated, (2) melatonin-treated, (3) untreated diabetic (UD), (4) melatonin-treated diabetic (MD). Experimental diabetes was induced by single dose (60 mg/kg, i.p.) STZ injection. For 3 days prior to administration of STZ, melatonin was injected (200 microg/kg/day, i.p.); these injections were continued until the end of the study (4 weeks). Malondialdehyde (MDA) levels as a marker of lipid peroxidation were significantly increased in the renal homogenates of UD animals and decreased after melatonin administration. The activity of the antioxidative enzyme glutathione peroxidase (GSH-Px) was significantly reduced in UD rats. Melatonin treatment reversed STZ-induced reduction of GSH-Px activity without having an effect on blood glucose. Upon histopathological examination, it was observed that the melatonin treatment prevented the renal morphological damage caused by diabetes. Upon immunohistochemical investigation, glomerular anti-laminin beta1 staining decreased in MD rats. Additionally, no tubular anti-IGF-1 staining was observed in melatonin-treated rats. In conclusion, chronically administered melatonin reduced renal injury in STZ-induced diabetic rats and thus it may provide a useful therapeutic option in humans to reduce oxidative stress and the associated renal injury in patients with diabetes mellitus.     

Effects of Trifolium alexandrinum extracts on streptozotocin-induced diabetes in male rats

The effects of (water, hexane and ethanolic) extracts prepared from the flower head of Trifolium alexandrinum (Leguminosae) were examined in the treatment of diabetes induced experimentally by streptozotocin (STZ) in rats. A single dose of STZ (50 mg/kg) produced a hyperglycemia, decrease in insulin level and elevation in glycosylated hemoglobin of RBCs as well as elevated serum total lipids, triglycerides and cholesterol levels. Also, a decreased serum high-density lipoprotein and in hepatic glycogen and glutathione GSH contents, concurrent with an increase in the concentration of malondialdehyde in the liver was observed. Daily intake of (water, hexane and ethanolic) extracts of T. alexandrinum in drinking water for 4 weeks immediately after diabetes induction caused significant decreases in glucose and glycated hemoglobin levels and increase in insulin level. It also greatly improved the levels of serum lipid parameters and significantly decreased lipid peroxidation in addition to increase the hepatic GSH content significantly. CONCLUSION: Extracts of T. alexandrinum improved hyperglycemia and other biochemical alterations noticed in STZ-diabetic rats. These effects may be due to the presence of a high content of flavonoids which acts synergistically as antioxidants.     

Utility of serum fructosamine as a measure of glycemia in young and old diabetic and non-diabetic subjects

PURPOSE: Currently used methods to determine glycemia have certain disadvantages, including cost, heavy labor involvement, and storage problems. Determination of serum fructosamine levels, on the other hand, offers several potential advantages over these current measures. Our goal was to evaluate the utility of serum fructosamine as a measure of glycemia. SUBJECTS AND METHODS: Fructosamine levels were measured in 145 normal and diabetic subjects aged 20 to 86 years. The measured levels were then related to standard measures of glycemia, including glycosylated hemoglobin, glycosylated albumin, and fasting glucose. The effects of chronic illness and medications known to alter glucose tolerance were also investigated. RESULTS: Fructosamine levels were well correlated with other measures: r = 0.73 with glucose, 0.76 with hemoglobin A1C (HbA1C), and 0.80 with glycosylated albumin. Levels of fructosamine were significantly higher (p less than 0.001) in diabetic subjects compared with those in non-diabetic subjects, but were not affected by age and were only minimally affected by chronic illness. Values for diabetic subjects with well-controlled and poorly controlled disease were also significantly different. CONCLUSION: Assay of serum fructosamine appears to be comparable to that of HbA1C for determination of glycemic control. The automaticity, reproducibility, and lower cost for the fructosamine assay argue strongly in favor of this assay in comparison to those for other glycosylated proteins.     

Comparative analysis of the protective effects of melatonin and vitamin E on streptozocin-induced diabetes mellitus

There is a clearly documented link between diabetic complications and lipid peroxidation. Hyperglycemia causes a reduction in levels of protective endogenous antioxidants and increases generation of free radicals. The present study was carried out to compare the protective effects of melatonin and vitamin E against streptozocin (STZ)-induced diabetes in rats. Melatonin was administered s.c. (100 microg/kg) whereas vitamin E was given i.p. (100 mg/kg) after induction of diabetes with STZ (60 mg/kg). Plasma total cholesterol, triglyceride and low density lipoprotein (LDL) levels were increased in STZ group while both melatonin and vitamin E injection caused a significant decrease in the levels of all these parameters. The lipid lowering effect of melatonin was greater than that of vitamin E. Melatonin caused a significant decrease in brain, liver and kidney tissue malondialdehyde (MDA) levels which were increased because of STZ-induced diabetes. Vitamin E also reduced elevated MDA concentrations in diabetic rat tissues, but the effect of melatonin was more potent than that of vitamin E. Furthermore, treatment of diabetic rats with melatonin increased brain and kidney glutathione peroxidase (GSH-Px) activity to the levels below that of control rats. Vitamin E was found to be less effective on GSH-Px activity levels in brain and kidney than melatonin whereas it was more potent than melatonin in liver. In summary, melatonin prevents many diabetic complications by reducing oxidative stress and protects organisms from oxidative damage and dyslipidemia. Considering the much lower molar concentration of melatonin compared with vitamin E, melatonin seems to be a more potent antioxidant, especially in the brain and kidney.     

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.     

Glycated proteins and cardiovascular disease in glucose intolerance and type 2 diabetes

Individuals with diabetes have more atherosclerosis and cardiovascular events and a higher complication rate from cardiovascular events than nondiabetic individuals. Also, lesions from diabetic patients are more prone to rupture and exhibit more intravascular thrombosis than those from nondiabetic patients. Glucose modification of circulating proteins and matrix proteins mediates the activation of the inflammatory pathways critical in diabetes-associated atherosclerosis. Extracellular matrix proteins containing advanced glycation end products (AGEs) serve as ligands for scavenger receptors and the receptor for AGEs. Ligation of the receptor for AGEs activates inflammatory pathways and destabilizes atherosclerotic plaques in diabetic patients. Clinically, researchers have used concentrations of fructosamine and glycosylated hemoglobin to investigate the relationships among glycemia, glucose-modified proteins, and cardiovascular risk. They found that increased levels of fructosamine and hemoglobin A_1c are associated with a significantly increased multivariable-adjusted risk of cardiovascular events.     

Protective effect of melatonin against oxidative stress induced by ligature of extra-hepatic biliary duct in rats: comparison with the effect of S-adenosyl-L-methionine

In the present research, we studied the effect of the administration of melatonin or S-adenosyl-L-methionine (S-AMe) on oxidative stress and hepatic cholestasis produced by double ligature of the extra-hepatic biliary duct (LBD) in adult male Wistar rats. Hepatic oxidative stress was evaluated by the changes in the amount of lipid peroxides and by the reduced glutathione content (GSH) in lysates of erythrocytes and homogenates of hepatic tissue. The severity of the cholestasis and hepatic injury were determined by the changes in the plasma enzyme activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), g-glutamyl-transpeptidase (GGT), and levels of albumin, total bilirubin (TB) and direct bilirubin (DB). Either melatonin or S-AMe were administered daily 3 days before LBD, and for 10 days after biliary obstruction. LDB caused highly significant increases in plasma enzyme activities and in bilirubin and lipid peroxides levels in erythrocytes and hepatic tissue. At the same time, this procedure produced a notable decrease in the GSH pools in these biological media. Both melatonin and S-AMe administration were effective as antioxidants and hepatoprotective substances, although the protective effects of melatonin were superior; it prevented the GSH decrease and reduced significantly the increases in enzyme activities and lipid peroxidation products produced by biliary ligature. S-AMe did not modify the increased GGT activity nor did it decrease greatly the TB levels (43% melatonin vs. 14% S-AMe). However, S-AMe was effective in preventing the loss of GSH in erythrocytes and hepatic tissue, as was melatonin. The obtained data permit the following conclusions. First, the LDB models cause marked hepatic oxidative stress. Second, the participation of free radicals of oxygen in the pathogenecity and severity of cholestasis produced by the acute obstruction of the extra-hepatic biliary duct is likely. Third, the results confirm the function of S-AMe as an antioxidant and hepatoprotector. Finally, melatonin is far more potent and provides superior protection as compared to S-AMe. Considering the decrease in oxidative stress and the intensity of cholestasis, these findings have interesting clinical implications for melatonin as a possible therapeutic agent in biliary cholestasis and parenchymatous liver injury.     

桑叶提取物对糖尿病小鼠心肌保护作用的研究

目的 基于氧化应激探究桑叶提取物(MLE)对糖尿病小鼠心肌保护作用及机制.方法 采用链脲佐菌素(STZ)及高糖脂饲料(HFD)诱导的糖尿病小鼠模型,以二甲双胍(Met,200 mg/kg)为阳性对照,分别给予100 mg/kg、200 mg/kg、400 mg/kg的桑叶提取物对糖尿病小鼠灌胃给药,干预12周后检测各组...     

Diabetes enhances oxidative stress-induced TRPM2 channel activity and its control by N-acetylcysteine in rat dorsal root ganglion and brain

N-acetylcysteine (NAC) is a sulfhydryl donor antioxidant that contributes to the regeneration of glutathione (GSH) and also scavengers via a direct reaction with free oxygen radicals. Recently, we observed a modulatory role of NAC on GSH-depleted dorsal root ganglion (DRG) cells in rats. NAC may have a protective role on oxidative stress and calcium influx through regulation of the TRPM2 channel in diabetic neurons. Therefore, we investigated the effects of NAC on DRG TRPM2 channel currents and brain oxidative stress in streptozotocin (STZ)-induced diabetic rats. Thirty-six rats divided into four groups: control, STZ, NAC and STZ + NAC. Diabetes was induced in the STZ and STZ + NAC groups by intraperitoneal STZ (65 mg/kg) administration. After the induction of diabetes, rats in the NAC and STZ + NAC groups received NAC (150 mg/kg) via gastric gavage. After 2 weeks, DRG neurons and the brain cortex were freshly isolated from rats. In whole-cell patch clamp experiments, TRPM2 currents in the DRG following diabetes induction with STZ were gated by H₂O₂. TRPM2 channel current densities in the DRG and lipid peroxidation levels in the DRG and brain were higher in the STZ groups than in controls; however, brain GSH, GSH peroxidase (GSH-Px), vitamin C and vitamin E concentrations and DRG GSH-Px activity were decreased by diabetes. STZ + H₂O₂-induced TRPM2 gating was totally inhibited by NAC and partially inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2-aminoethyl diphenylborinate (2-APB). GSH-Px activity and lipid peroxidation levels were also attenuated by NAC treatment. In conclusion, we observed a modulatory role of NAC on oxidative stress and Ca²⁺ entry through the TRPM2 channel in the diabetic DRG and brain. Since excessive oxidative stress and overload Ca²⁺ entry are common features of neuropathic pain, our findings are relevant to the etiology and treatment of pain neuropathology in DRG neurons.     

Postprandial glucose regulation and diabetic complications

Atherosclerotic disease accounts for much of the increased mortality and morbidity associated with type 2 diabetes. Epidemiological studies support the potential of improved glycemic control to reduce cardiovascular complications. An association between glycosylated hemoglobin (HbA(1c)) level and the risk for cardiovascular complications has frequently been reported. Most epidemiological data implicate postprandial hyperglycemia in the development of cardiovascular disease, whereas the link between fasting glycemia and diabetic complications is inconclusive. Moreover, in many studies, postprandial glycemia is a better predictor of cardiovascular risk than HbA(1c) level. Postprandial glucose may have a direct toxic effect on the vascular endothelium, mediated by oxidative stress that is independent of other cardiovascular risk factors such as hyperlipidemia. Postprandial hyperglycemia also may exert its effects through its substantial contribution to total glycemic exposure. The present review examines the hypothesis that controlling postprandial glucose level is an important strategy in the prevention of cardiovascular complications associated with diabetes.     

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     

Genotoxicity evaluation in severe or mild diabetic pregnancy in laboratory animals

This study aimed to evaluate the genotoxicity (DNA damage levels) in lymphocyte samples from pregnant Wistar rats with severe or mild diabetes and in whole blood samples from their newborns. Wistar female rats (1 and 90 days of age) and male rats (approximately 90 days of age) were used. The experiment consisted of 2 experimental groups (n=8 animals/group): 1) rats with severe diabetes, 2) rats with mild diabetes. For mild diabetes induction, the rats received streptozotocin (STZ) subcutaneously (100 mg/kg body weight) at day of birth, and those showing glycemia from 120 to 300 mg/dL in their adult life were included. For induction of severe diabetes, adult rats received 40 mg/kg STZ (intravenous route), and those showing glycemia > 300 mg/dL were included. At day 21 of pregnancy, the rats were anesthetized and euthanized for removal of maternal and fetal blood samples for determination of the oxidative DNA damage by applying Endo III and Fpg using the comet assay. Thus, the rats with mild diabetes and their offspring showed higher Fpg-sensitive sites, reflecting the damage resulting from hyperglycemia. The rats with severe diabetes and their offspring showed higher oxidative DNA damage detected by Fpg and Endo III-sensitive sites, showing general repercussions related to diabetes. The enzymatic treatment for DNA damage evidenced that the maternal repercussions of diabetes are associated with oxidative DNA damage of their newborn, which was not reflected using only the analysis of DNA damage free of the enzymes.     

Melatonin reduces oxidative stress in erythrocytes and plasma of senescence-accelerated mice

It has been suggested that oxidative stress is a feature of aging. The goal of the present study was to assess the oxidant effects related to aging and the protective role of exogenous melatonin in senescence-accelerated mice (SAMP8). Two groups of SAMP8 mice (males and females) were compared with their respective control groups of SAMR1 mice (senescence-resistant inbred strain) to determine their oxidative status without melatonin treatment. Four other groups of the same characteristics were treated with melatonin (10 mg/kg/day) in their drinking water. The melatonin concentration in the feeding bottles was titrated according to water consumption and body weight (i.e. 0.06 mg/mL for 30 g of body weight and 5 mL/day of water consumption). The treatment began when animals were 1-month old and continued for 9 months. When mice were 10-month old, they were anesthetized and blood was obtained. Plasma and erythrocytes were processed to examine oxidative stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), glutathione S-transferase (GST), thiobarbituric acid reactive substances (TBARS), and hemolysis. The results showed greater oxidative stress in SAMP8 than in SAMR1, largely because of a decrease in GSH levels and to an increase in GSSG and TBARS with the subsequent induction of the antioxidant enzymes GPX and GR. Melatonin, as an antioxidant molecule, improved the glutathione-related parameters, prevented the induction of GPX in senescent groups, and promoted a decrease in SOD and TBARS in almost all the groups.     

Insulin decreases intracellular oxidative stress in patients with type 2 diabetes mellitus

Patients affected by diabetes mellitus have oxidative stress with an impaired glutathione (GSH) redox state. The objective of this study was to determine the influence of insulin on oxidative stress, defined as a reduced intracellular GSH/GSH disulfide (GSSG) ratio and lipid peroxidation by plasma thiobarbituric acid reactive substances (TBARSs) in patients with type 2 diabetes. Two experimental interventions were used: (1) measurement of GSH/GSSG ratio after insulin incubation in erythrocytes from 10 type 2 diabetic patients, and (2) measurement of intraerythrocytic GSH/GSSG ratio and plasma TBARS in 14 type 2 diabetic patients during an in vivo hyperinsulinemic condition obtained from a euglycemic hyperinsulinemic clamp study. We confirmed that our patients underwent oxidative stress as shown by the significant difference in intracellular GSH/GSSG ratio in diabetic patients as compared to controls (13.56+/-3.84 vs 27.89+/-8.37, P<.0001). We found a significant elevation in the GSH/GSSG ratio after 2 hours of incubation with insulin in erythrocytes from diabetic patients (11.56+/-1.98 to 15.61+/-2.62, P<.001). During the clamp studies, GSH/GSSG ratio had already increased after 60 minutes and even more after 120 minutes (baseline, 15.04+/-4.19; at 60 minutes, 19.74+/-6.33; at 120 minutes, 25.33+/-11.15; P<.0001). On the contrary, no significant changes were observed in plasma TBARS (3.59+/-0.77 to 3.56+/-0.83, NS). We conclude that insulin in patients with type 2 diabetes mellitus can reduce intracellular oxidative stress through increased GSH/GSSG ratio.     

Protective melatonin effect on oxidative stress induced by okadaic acid into rat brain

We studied the effect of melatonin on the oxidative changes produced by the intracerebroventricular (i.c.v.) injection of okadaic acid (200 ng/kg BW) in the Wistar rat. The effects of okadaic acid were evaluated as changes in the quantity of lipid peroxides, reduced glutathione content (GSH) and activity of antioxidative enzymes. Okadaic acid caused lipid peroxidation (5.35 +/- 0.47 micro mol/g tissue in the i.c.v. vehicle group versus 10.14 +/- 0.88 micro mol/g tissue in the okadaic acid group, P < 0.001), GSH consumption (0.115 +/- 0.0065 micro mol/g tissue in the i.c.v. vehicle group versus 0.024 +/- 0.0021 micro mol/g tissue, P < 0.001), and a reduction in the activity of GSH-peroxidase, GSH-reductase and GSH-transferase between 60-80%. All these changes were prevented by pre-injection of 4.5 mg melatonin per kg BW 2 hr before okadaic acid. These findings indicate: (i) okadaic acid induces a status of oxidative stress in the brain, characterized by a high level of lipid peroxidation, decreases in GSH content and diminished activities of antioxidative enzymes, and (ii) melatonin prevents the deleterious effects induced by okadaic acid. In conclusion, the results show the ability of melatonin to modify the neural response to okadaic acid with the protective mechanism likely involving the antioxidative processes of melatonin.     

Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats

Abnormal regulation of glucose and impaired carbohydrate utilization that result from a defective or deficient insulin are the key pathogenic events in type 2 diabetes mellitus (T2DM). The present study was hypothesized to investigate the beneficial effects of hesperidin and naringin on hyperglycemia-induced oxidative damage in HFD/STZ-induced diabetic rats. Diabetes was induced by feeding rats with an HFD for 2 weeks followed by an intraperitoneal injection of STZ (35 mg/kg body weight). An oral dose of 50 mg/kg hesperidin or naringin was daily given for 4 weeks after diabetes induction. At the end of the experimental period, blood was obtained from jugular vein and livers were rapidly excised and homogenized for biochemical assays. In the diabetic control group, levels of glucose, glycosylated hemoglobin (HbA1c%), MDA, NO, TNF-α and IL-6 were significantly increased, while serum insulin, GSH, vitamin C, and vitamin E levels were decreased. Both hesperidin and naringin administration significantly reversed these alterations. Moreover, supplementation with either compound significantly ameliorated serum and liver MDA, NO and glutathione, and liver antioxidant enzymes. Although detailed studies are required for the evaluation of the exact mechanism of the ameliorative effects of hesperidin and naringin against diabetic complications, these preliminary experimental findings demonstrate that both hesperidin and naringin exhibit antidiabetic effects in a rat model of T2DM by potentiating the antioxidant defense system and suppressing proinflammatory cytokine production.     

Melatonin versus vitamin E as protective treatment against oxidative stress after extra-hepatic bile duct ligation in rats

The aims of the present study were first to compare the effects of melatonin and vitamin E on the cholestasis syndrome and their protective effect on liver injury, and second, to evaluate the activity of antioxidant enzymes after treatment with these antioxidant drugs. Cholestasis was achieved in adult male Wistar rats by double ligature and section of the extra-hepatic biliary duct. Hepatic and plasma oxidative stress markers were evaluated by changes in the amount of lipid peroxides, measured as malondialdehyde (MDA) and reduced glutathione (GSH) in plasma and homogenates of hepatic tissue. Serum bilirubin, alkaline phosphatase (AP), and gamma-glutamyl-transpeptidase (GGT) were used to evaluate the severity of cholestasis, and serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were used to evaluate the hepatic injury. Both vitamin E and melatonin were administrated 1 day before and 7 days after bile duct ligation. Acute ligation of the bile duct was accompanied by a significant increased in MDA and a decrease in GSH levels in both plasma and liver, as well as a significant reduction in antioxidant enzymes activities. The overall analysis of both treatments showed that melatonin (500 microg/kg daily) offered significantly better protection against cholestasis and a superior protective effect on hepatic injury than did vitamin E (15 mg/kg daily). Although vitamin E treatment resulted in a reduction of parameters of oxidative stress, the results were significantly better after a much lower daily dose of melatonin. Moreover, melatonin treatment was associated with a significant recovery of antioxidative enzymes. In conclusion, the present paper demonstrates a correlation between the intensity of biliary tract obstruction and increased free radical generation, as well as a direct correlation between the level of oxidative stress and the biochemical markers of liver injury. Melatonin (at a much lower dose than vitamin E) was much more efficient than vitamin E in reducing the negative parameters of cholestasis, the degree of oxidative stress and provided a significantly greater hepatoprotective effect against the liver injury secondary to the acute ligation of the biliary duct.     

Dual effects of melatonin on oxidative stress after surgical brain injury in rats

Abstract:  The purpose of this study was to evaluate the effect of melatonin on oxidative stress occurring in the brain after routine lobectomy neurosurgery procedures. Different concentrations of melatonin (5, 15 and 150 mg/kg) were administered 1 hr before lobectomy in a rodent surgical brain injury (SBI) model. Neurological outcomes were assessed 24 hr before the killing of the rodents, for evaluation of brain water content (brain edema) and lipid peroxidation (oxidative stress). The results showed that lower doses (5 and 15 mg/kg) failed to reduce brain edema, but the 15 mg/kg dose did lower oxidative stress and improved several neurological parameters. High concentration of melatonin (150 mg/kg) significantly increased brain edema and elevated oxidative stress when compared with the vehicle-treated group. Furthermore, high-dose melatonin also worsened neurological outcomes compared with other groups. The study suggests that melatonin has dual effects: low-dose melatonin may provide neuroprotective effects against SBI but a high dose may aggravate some parameters after SBI.