Protective efficacy and the recovery profile of certain chemoprotectants against lethal poisoning by microcystin-LR in mice.

The cyclic peptide toxins microcystins and nodularins are the most common and abundant cyanotoxins present in diverse water systems. They have been the cause of human and animal health hazards and even death. Development of suitable chemoprotectants against microcystin is essential considering the human health importance. In the present study, three agents cyclosporin-A (10mg/kg), rifampin (25mg/kg) and silymarin (400mg/kg) pre-treatment gave 100% protection against lethal dose of microcystin-LR (100 microg/kg). Various biochemical parameters were evaluated to study the recovery profile of protected animals at 1, 3, 7 and 14 days post-toxin treatment. There was significant depletion of hepatic glutathione in protected animals compared to control group till 7 days post-treatment but normalised by 14 days. Similarly enhanced hepatic lipid peroxidation, inhibition of protein phosphatase activity was observed till 3-7 days post-treatment in protected animals. Elevated levels of enzymes alanine amino transferase, lactate dehydrogenase and sorbitol dehydrogenase were observed in serum at 1 day post-treatment. All the biochemical variables reached control levels by 14 day post-treatment. Immunoblotting analyses of liver homogenates showed microcystin-protein phosphatase adduct in liver samples of toxin treated as well as antidote-protected animals. The adduct could be seen even after 14 days post-toxin treatment. The study shows that though cyclosporin-A, rifampin and silymarin could offer 100% protection against microcystin-LR induced lethality many of the toxic manifestations are persistent and could not be reversed till 7 days.     

The flavonolignan‐silymarin protects enzymatic,hematological, and immune system against γ‐radiation‐induced toxicity

The main focus of this study is evaluation of radioprotective efficacy of silymarin, a flavonolignan, against γ‐radiation‐induced damage to hematological, vital organs (liver and intestine), and immune system. Survival studies revealed that silymarin (administered orally for 3 days) provided maximum protection (67%) at 70 mg/kg body weight (b.wt.) against lethal 9 Gy γ‐irradiation (dose reduction factor = 1.27). The study revealed significant (p < 0.05) changes in levels of catalase (12.57 ± 2.58 to 30.24 ± 4.89 units), glutathione peroxidase (6.23 ± 2.95 to 13.26 ± 1.36 µg of reduced glutathione consumed/min/mg protein), glutathione reductase (0.25 ± 5.6 to 11.65 ± 2.83 pM NADPH consumed/min/mg protein), and superoxide dismutase (11.74 ± 0.2 to 16.09 ± 3.47 SOD U/mg of protein) activity at 30th day. Silymarin pretreated irradiated group exhibited increased proliferation in erythrocyte count (1.76 ± 0.41 × 10⁶ to 9.25 ± 0.24 × 10⁶), hemoglobin (2.15 ± 0.48g/dL to 14.77 ± 0.25g/dL), hematocrit (4.55 ± 0.24% to 37.22 ± 0.21%), and total leucocyte count (1.4 ± 0.15 × 10⁶ to 8.31 ± 0.47 × 10⁶) as compared with radiation control group on 15th day. An increase in CD4:CD8 ratio was witnessed (0.2–1%) at 30th day time interval using flow cytometry. Silymarin also countered radiation‐induced decrease (p < 0.05) in regulatory T‐cells (T_regs) (11.23% in radiation group at 7th day versus 0.1% in pretreated silymarin irradiated group at 15th day). The results of this study indicate that flavonolignan‐silymarin protects enzymatic, hematological, and immune system against γ‐radiation‐induced toxicity and might prove useful in management of nuclear and radiological emergencies. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 641–654, 2016.     

Manipulation of mouse organ glutathione contents. II: Time and dose-dependent induction of the glutathione conjugation system by phenolic antioxidants

After 14 days of oral butylated hydroxyanisole (BHA) administration (1000 mg/kg/day) the tissue glutathione levels of male NMRI mice were increased by 74-141% in liver, lung, duodenum and intestine and after similar butylated hydroxytoluene (BHT) treatment by 18-85% in the liver, lung, spleen and the gastrointestinal tract. Doses of 100 mg/kg/day significantly elevated the glutathione content in the lung (BHA, BHT), duodenum (BHA) and intestine (BHA), while 10 mg/kg/day affected only lung glutathione content (BHA). BHA treatment (1000 mg/kg/day) induced GST activities significantly (138-1335%) in all organs investigated except the spleen, i.e. liver, lung, kidney and the entire gastrointestinal tract, while a similar dose of BHT increased GST activities in the liver, duodenum, intestine and colon by 26-339%. Daily doses of 100 mg/kg/day significantly induced GST activities only in the liver (BHA, BHT), lung (BHA) and kidney (BHA). Lower doses of BHA or BHT did not significantly affect GST activities in the organs investigated (except 10 mg BHA/kg/day in the lung). Comparison of the time course of induction of the glutathione conjugation system in various organs after different doses of antioxidants indicated no change between 5 and 14 days of treatment with all doses used (1-1000 mg/kg). Only the lung glutathione level showed a tendency to increase with low dose BHA by extending the time of treatment. The time course of the liver glutathione content between single doses of 100 mg/kg BHA or BHT revealed an initial decline followed by an increase above control values 2 days (BHA) or 5 days (BHT) after the first application. The glutathione levels of the lung and the duodenum increased without a preceding decline. Only the second dose of BHT caused a temporary decrease to control values of the elevated glutathione level in the duodenum. All animals (at any dose of BHA or BHT) showed control values of serum transaminase activities. These results suggest: The induction threshold of the glutathione conjugation system in various mouse organs is greater than or equal to 100 mg/kg for BHA and BHT. Chronic administration of these compounds did not change these results (except the lung glutathione level after low dose BHA). Elevated hepatic glutathione levels might be the result of an activated synthesis caused by a preceding loss of glutathione. Chronic BHA or BHT treatment did not cause hepatotoxic effects, as evaluated by serum transaminases, in male mice.     

Protective effect of alpha-lipoic acid against chloroquine-induced hepatotoxicity in rats

Oral administration of a-lipoic acid, a metavitamin, was investigated for its possible hepatoprotective effect in Wistar rats against chloroquine-induced toxicity. Rats were treated orally with alpha-lipoic acid (10, 30 and 100 mg x kg(-1) day(-1)) for 7 days before a single oral administration of chloroquine (970 mg x kg(-1) day(-1)) and alpha-lipoic acid treatment was continued for three more days. The increased level of serum enzymes (aspartate transaminase, alanine transaminase and alkaline phosphatase), bilirubin, lipids and plasma thiobarbituric acid-reactive substances (TBARS) and hydroperoxides observed in rats treated with chloroquine were very much reduced in rats treated with alpha-lipoic acid plus chloroquine. A significant decrease in plasma antioxidants such as reduced glutathione (GSH), vitamin C and vitamin E were observed in chloroquine-treated rats when compared with control rats. Administration of alpha-lipoic acid significantly improved the levels of plasma antioxidants GSH, vitamin C and vitamin E in chloroquine-treated rats. In the case of 100 mg x kg(-1) day(-1) the effect was highly significant compared with the other doses (10 and 30 mg x kg(-1) day(-1)). The results of the study revealed that alpha-lipoic acid could offer protection against chloroquine-induced hepatotoxicity. alpha-Lipoic acid had a better protective effect when compared with silymarin, a reference drug.     

Acetaminophen-induced Hepato- and Nephrotoxicity and Amelioration by Silymarin and Terminalia chebula in Rats

Experimental study was conducted to evaluate the hepato- and renoprotective effect of silymarin and Terminalia chebula against experimentally-induced acetaminophen (APAP) toxicity in rats. Oral administration of APAP @ 500 mg/kg for 1 to 3 days to all the four groups (six rats in each) resulted in significant elevation of serum triglycerides, total cholesterol, blood urea nitrogen, serum creatinine, and aspartate transaminase activity. Post-treatment with silymarin @ 25 mg/kg and T. chebula 125 mg/kg in groups 2 and 3 and their combination to group 4 from day 4 to 14 has significantly reversed the alterations of above said markers and offered better protection. The results of the study enunciated that silymarin and T. chebula exhibit good hepato- and nephro-protection against APAP toxicity.     

Antifibrotic activity of hesperidin against dimethylnitrosamine-induced liver fibrosis in rats

Hepatic fibrosis is a significant health problem that may progress to cirrhosis and cancer. It may be caused by viruses or chemicals such as dimethylnitrosamine, which is used as a preservative in processed meats and industrial products. The present study was designed to investigate the antifibrotic effect of hesperidin (100 or 200 mg/kg, a flavanone glycoside with potent anti-inflammatory and antioxidant activities) against liver fibrosis in rats compared to silymarin (100 mg/kg). Liver fibrosis was induced in rats using dimethylnitrosamine (10 mg/kg/day, i.p.) three times per week on alternating days for 4 weeks. After 28 days, tissue and blood samples were collected to assess the protective effect of hesperidin. Dimethylnitrosamine caused liver fibrosis as evidenced by the elevation in the levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total and direct bilirubin, as well as hepatic malondialdehyde content, gene expression of inducible nitric oxide synthase, α-smooth muscle actin and caspase-3. In addition, dimethylnitrosamine caused a reduction in serum total protein, albumin and hepatic glutathione content. Treatment with hesperidin (100 or 200 mg/kg) successfully ameliorated the deleterious effects of dimethylnitrosamine on all tested parameters. Our study indicates a novel protective effect of hesperidin against dimethylnitrosamine-induced liver fibrosis. Interestingly, the protection evoked by hesperidin (200 mg/kg) was superior to that of the standard silymarin.     

Post-irradiation effect of Broncho-Vaxom, OM-85 BV, and its relationship to anti-oxidant activities

This study was conducted to test the efficacy of Broncho-Vaxom (OM-85 BV) in rats after exposure to radiation-induced oxidative stress. Daily administration of Broncho-Vaxom (2.5 mg/kg/day) to rats for a period of 28 days produced a progressive significant increase in the activities of superoxide dismutase (SOD) and catalase in lungs and erythrocytes. No changes were recorded in reduced glutathione (GSH) content in lungs, while an increase was recorded in erythrocytes. Significant increase was also observed in serum gamma-globulin content. Intraperitoneal administration of Broncho-Vaxom to rats for 11 days before gamma-irradiation and daily during the period of irradiation, delivered as 1 Gy every other day to reach 9 Gy, significantly reduced radiation-induced lipid peroxidation (LPO) measured as thiobarbituric acid-reactive substances (TBARS) in the lungs and erythrocytes. Treatment with Broncho-Vaxom modified the radiation-induced decrease of serum gamma-globulins contents. It is postulated that Broncho-Vaxom, by enhancing the antioxidant system and increasing serum gamma-globulin content, could play an important role in modifying radiation-induced oxidative stress.     

Silymarin protects against paracetamol-induced lipid peroxidation and liver damage.

The effect of silymarin on liver damage induced by acetaminophen (APAP) intoxication was studied. Wistar male rats pretreated (72 h) with 3-methylcholanthrene (3-MC) (20 mg kg-1 body wt. i.p.) were divided into three groups: animals in group 1 were treated with acetaminophen (APAP) (500 mg kg-1 body wt. p.o.), group 2 consisted of animals that received APAP plus silymarin (200 mg kg-1 body wt. p.o.) 24 h before APAP, and rats in group 3 (control) received the equivalent amount of the vehicles. Animals were sacrificed at different times after APAP administration. Reduced glutathione (GSH), lipid peroxidation and glycogen were measured in liver and alkaline phosphatase (AP), gamma-glutamyl transpeptidase (GGTP) and glutamic pyruvic transaminase (GPT) activities were measured in serum. After APAP intoxication, GSH and glycogen decreased very fast (1 h) and remained low for 6 h. Lipid peroxidation increased three times over the control 4 and 6 h after APAP treatment. Enzyme activities increased 18 h after intoxication. In the group receiving APAP plus silymarin, levels of lipid peroxidation and serum enzyme activities remained within the control values at any time studied. The fall in GSH was not prevented by silymarin, but glycogen was restored at 18 h. It was concluded that silymarin can protect against APAP intoxication through its antioxidant properties, possibly acting as a free-radical scavenger.     

Comparison of early treatment with low doses of nilotinib, imatinib and a clinically relevant dose of silymarin in thioacetamide-induced liver fibrosis

Our previous study has already confirmed a promising anti-fibrotic activity especially for nilotinib; when given at a daily dose of 10 mg/kg during the last 4 weeks of thioacetamide (TAA)-induced liver fibrosis for 12 weeks in rats. Therefore, this study was carried out to compare the prophylactic potential of low dose of nilotinib to that of its predecessor, imatinib, and a clinically relevant dose of the standard hepatoprotective treatment, silymarin, in TAA-intoxication. Male Wistar rats received intraperitoneal injections of TAA (150 mg/kg, twice weekly) for 8 weeks, as well as oral treatments with imatinib (5 mg/kg/day), nilotinib (5 mg/kg/day) and silymarin (50 mg/kg/day) from the first day of TAA-intoxication. At the end of the study, chronic hepatic injury was evaluated by analysis of liver function tests in serum. Hepatic oxidative stress was assessed by measuring malondialdehyde, 4-hydroxynonenal, total nitrate/nitrite and reduced glutathione contents, as well as myeloperoxidase and superoxide dismutase activities. Hepatic fibrosis was evaluated by histopathology and collagen content. Our results suggest that the prophylactic potential of nilotinib (5 mg/kg/day), imatinib (5mg/kg/day) and silymarin (50 mg/kg/day) in TAA-intoxication for 8 weeks is lower than the late treatments of nilotinib (10 mg/kg/day), imatinib (10mg/kg/day) and silymarin (100 mg/kg/day) during the last 4 weeks of TAA-intoxication for 12 weeks in rats. Taken together, this study suggests that nilotinib may have higher anti-fibrotic activity when administered at a significant stage of fibrosis as a result of impairment of its metabolism in the fibrotic livers.     

Hepatoprotective activity of methanolic extract of Hiptage bengalensis leaves against CCl₄-induced hepatotoxicity in rats

The objective of the present study was to evaluate hepatoprotective activity of methanolic extract of Hiptage bengalensis (L.) kurz (MEHB) in rats. Hepatic damage was induced by administration of carbontetrachloride(1 ml/kg, b.w, p.o.) in combination with liquid paraffin (1:1) as a single dose on 7th day. The extent of liver damage was studied by estimating biochemical parameters. Administration of MEHB (200 mg & 400 mg/kg) for 6 days before carbontetrachloride administration showed a significant reduction (p < 0.01) of serum liver damage enzymes markers-aspartate transaminase, alanine transaminase, total bilirubin and alkaline phosphatase (ALP). Histopathological changes of hepatic tissue were also evaluated in control and MEHB treated groups. Results also indicated that MEHB possessed potential antioxidant effect by increasing the levels of glutathione and also possessed free radical scavenging activities. The hepatoprotective effect of Hiptage bengalensis (L.) kurz was comparable to standard drug silymarin (50 mg/kg).     

Protective mechanism of salvia miltiorrhiza on carbon tetrachloride-induced acute hepatotoxicity in rats

The purpose of this study was to investigate the possible mechanisms of Salvia miltiorrhiza (Sm) in carbon tetrachloride (CCl(4))-induced acute hepatotoxicity in rats. Male Wistar rats received a single dose of CCl(4) (2 ml/kg in corn oil, intraperitoneally). Three hours after CCl(4) intoxication, rats received either Sm (100 mg/kg) or silymarin (100 mg/kg) by gastrogavage twice a day for 2 consecutive days. CCl(4)-induced liver damage was shown by significant elevation of serum aminotransferase levels. Additionally, a significant decrease was observed in hepatic microsomal P450 2E1 protein content and hepatic concentrations of antioxidant enzymes. In contrast, rats given both Sm and silymarin supplement had less elevation of serum aminotransferase concentrations associated with less severe lobular damage of hepatocytes than rats receiving CCl(4) alone. Sm administration restored the reduction of hepatic microsomal P450 2E1 protein content as well as inducing an increase in hepatic glutathione concentration. On the other hand, administration of silymarin resulted in an elevation of hepatic superoxide dismutase levels. Moreover, both Sm and silymarin treatment inhibited the elevation of hepatic inducible nitric oxide (iNOS) protein content and nitrite concentration in liver homogenate 24 h after CCl(4) intoxication. We concluded that administration of Sm is effective in amelioration of CCl(4)-induced hepatotoxicity. This effect may be due to its ability to decrease the metabolic activation of CCl(4) by an increase in P450 2E1 protein content and its antioxidant activity associated with less increase in hepatic iNOS protein content.     

Hepatoprotective efficacy of certain flavonoids against microcystin induced toxicity in mice

Toxic cyanobacteria (blue-green algae) water blooms have become a serious problem in several industrialized areas of the world. Microcystin-LR (MC-LR) is a cyanobacterial heptapeptide that represents acute and chronic hazards to animal and human health. Identification of suitable chemprotectants against microcystin is essential considering human health hazards. In the present study, we have evaluated the protective efficacy of three flavanoids namely quercetin (200 mg/kg), silybin (400 mg/kg), and morin (400 mg/kg)] pretreatment against microcystin toxicity (0.75 LD(50), 57.5 microg/kg) in mice. Various biochemical variables were measured to study the recovery profile of protected animals at 1- and 3-days post-toxin treatment. The serum alanine amino transferase (ALT) shows 17-fold increase in MC-LR treated animals compared with control group at 1 day. The silybin and quercetin group showed a decrease in level of ALT compared with MC-LR group but still higher than control group. No significant protection was observed with aspartate aminotransaminase (AST) and lactate dehydrogenase (LDH) levels in flavanoid-treated groups at 1-day post-treatment. But at 3 days, the serum levels of AST and ALT were normalized to control values, but the serum LDH levels were still significantly higher than the control group. No significant changes were observed in glutathione peroxidase and reduced glutathione levels at both 1- and 3-day postexposure. The catalase activity shows a significant decrease in quercetin-treated animals at 3-day postexposure. The protein phosphatase was significantly inhibited in MC-LR group compared to control. The silybin pretreated group showed recovery after 1 day. At 3 days, the PPAse activity was reversed to control values in all the flavanoid-treated groups. Immunoblotting analysis showed microcystin-PPAse adduct in liver tissues of toxin-treated as well as flavanoid-treated mice even after 3 days. The results of this study show that flavanoids, quercetin, silybin, and morin could reverse the hepatotoxic effects of MC-LR in vivo.     

Comparison of behavioral and radioprotective effects of WR-2721 and WR-3689.

The behavioral effects of the radioprotectant agents ethiofos, S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) and S-2-(3-methylaminopropyl)aminoethylphosphorothioic acid (WR-3689) were evaluated in rats trained to respond under a multiple fixed-interval 120-s, fixed-ratio 50-response (mult FI FR) schedule of milk reinforcement. Each compound produced dose-dependent reductions in responding under both schedules over the same dose range (100-180 mg/kg, IP); ED50s indicated that WR-3689 was slightly more potent than WR-2721. On several performance measures, WR-3689 produced greater decrements during a second dose-effect determination, whereas WR-2721 had more pronounced effects during the initial one. In a second series of studies, low (56 mg/kg) and high (180 mg/kg) doses of both drugs were tested for radioprotective effects in rats responding under an FR-50 schedule of milk reinforcement and exposed to a nonlethal (5 gray, Gy) or lethal (10 Gy) dose of ionizing radiation (60Co gamma rays). Neither dose of radiation altered FR response rates on the day of exposure (day 1). Five Gy of gamma radiation produced a 25-40% reduction in response rates on days 2-5 (24-72 h) after exposure. Neither dose of WR-2721 or WR-3689 provided significant protection against these performance decrements. All groups exposed to 10 Gy experienced a progressive decline in FR responding on days 2-5 after exposure. Performance of groups that received pretreatment with the 180-mg/kg dose of either drug or the 56-mg/kg dose of WR-3689 was maintained at significantly higher levels than saline-treated controls on days 4-5 after exposure to 10 Gy; however, even at these higher levels of performance response rates remained below 50% of preirradiation control levels. Subsequently, 56 and 180 mg/kg WR-3689 and 180 mg/kg WR-2721 were found to provide protection against the lethal consequences of the 10-Gy exposure. Thus, neither WR-2721 nor WR-3689 afforded any significant short-term protection against radiation-induced performance decrements when these drugs were administered at either behaviorally ineffective or behaviorally disruptive doses. Rather, the beneficial effects of these drugs paralleled their ability to antagonize radiation-induced lethality.     

Hepatoprotective activity of methanolic extract of Hiptage bengalensis leaves against CCl4-induced hepatotoxicity in rats

The objective of the present study was to evaluate hepatoprotective activity of methanolic extract of Hiptage bengalensis (L.) kurz (MEHB) in rats. Hepatic damage was induced by administration of carbontetrachloride(1 ml/kg, b.w, p.o.) in combination with liquid paraffin (1:1) as a single dose on 7th day. The extent of liver damage was studied by estimating biochemical parameters. Administration of MEHB (200 mg & 400 mg/kg) for 6 days before carbontetrachloride administration showed a significant reduction (p < 0.01) of serum liver damage enzymes markers-aspartate transaminase, alanine transaminase, total bilirubin and alkaline phosphatase (ALP). Histopathological changes of hepatic tissue were also evaluated in control and MEHB treated groups. Results also indicated that MEHB possessed potential antioxidant effect by increasing the levels of glutathione and also possessed free radical scavenging activities. The hepatoprotective effect of Hiptage bengalensis (L.) kurz was comparable to standard drug silymarin (50 mg/kg).     

Biochemical and immunological basis of silymarin effect, a milk thistle (Silybum marianum) against ethanol-induced oxidative damage

Ethanol metabolism induces generation of excessive amount of reactive oxygen species (ROS) which results in immune dysfunction. We examined the efficacy of silymarin on ethanol-induced oxidative stress, immunomodulatory activity, and vascular function in mice blood. Effectiveness of silymarin was compared with potent antioxidant ascorbic acid. In the present study, 8- to 10-week-old male BALB/c mice (20-30 g) were divided into the four groups of six each. One group were fed with ethanol (1.6 g/kg body weight), while second group were fed with ethanol (1.6 g/kg body weight) and silybin (250 mg/kg body weight), and the third group were exposed to ethanol (250 mg/kg body weight) and ascorbic acid (250 mg/kg body weight) per day for 12 weeks. The control group was fed with isocaloric glucose solution instead of ethanol. Ethanol exposure significantly increased thiobarbituric acid reactive substance (TBARS) and nitrite levels besides glutathione-S-transferase (GST) activity, and significantly decreased reduced glutathione (GSH) content and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) in whole blood hemolyzate, while silymarin treatment significantly normalized these altered parameters. Silymarin significantly prevented ethanol-induced, elevated activities of interleukin (IL)-10, tumor necrosis factor (TNF)-α, γ interferon (IFN-γ), vascular endothelial growth factor (VEGF)-A, and transforming growth factor (TGF)-β1, as well as decreased IL-4 activity in mice blood. These results were comparable with the activity of ascorbic acid.     

Biochemical and immunological basis of silymarin effect,a milk thistle (Silybum marianum) against ethanol-induced oxidative damage

Ethanol metabolism induces generation of excessive amount of reactive oxygen species (ROS) which results in immune dysfunction. We examined the efficacy of silymarin on ethanol-induced oxidative stress, immunomodulatory activity, and vascular function in mice blood. Effectiveness of silymarin was compared with potent antioxidant ascorbic acid. In the present study, 8- to 10-week-old male BALB/c mice (20–30 g) were divided into the four groups of six each. One group were fed with ethanol (1.6 g/kg body weight), while second group were fed with ethanol (1.6 g/kg body weight) and silybin (250 mg/kg body weight), and the third group were exposed to ethanol (250 mg/kg body weight) and ascorbic acid (250 mg/kg body weight) per day for 12 weeks. The control group was fed with isocaloric glucose solution instead of ethanol. Ethanol exposure significantly increased thiobarbituric acid reactive substance (TBARS) and nitrite levels besides glutathione-S-transferase (GST) activity, and significantly decreased reduced glutathione (GSH) content and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) in whole blood hemolyzate, while silymarin treatment significantly normalized these altered parameters. Silymarin significantly prevented ethanol-induced, elevated activities of interleukin (IL)-10, tumor necrosis factor (TNF)-α, γ interferon (IFN-γ), vascular endothelial growth factor (VEGF)-A, and transforming growth factor (TGF)-β1, as well as decreased IL-4 activity in mice blood. These results were comparable with the activity of ascorbic acid.     

A 90-day drinking water toxicity study in rats of the environmental contaminant ammonium perchlorate.

Perchlorate (ClO(4)(-)), the dissociated anion of perchlorate salts such as ammonium, potassium, and sodium perchlorate, has been recently recognized as a persistent and pervasive contaminant of drinking water supplies in a number of metropolitan areas. Perchlorate is of concern because of uncertainties in the toxicological database available to address the potential human health effects of low-level exposure. The purpose of this study was to evaluate the subchronic toxicity of perchlorate when administered to Sprague-Dawley rats as ammonium perchlorate (AP) for 14 or 90 days. The study consisted of an untreated control group and five treatment groups that received continuous exposure to AP via the drinking water at dosage levels of 0.01, 0.05, 0.2, 1.0, and 10.0 mg/kg/day. The study design included a nontreatment recovery period of 30 days to evaluate the reversibility of any AP-induced effects at the 0.05, 1.0, and 10.0 mg/kg/day levels. The study also investigated the potential effects of AP on male sperm parameters, female estrous cyclicity, bone marrow micronucleus formation, and serum hormone levels, i.e., triiodothyronine (T(3)), thyroxine (T(4)), and thyroid stimulating hormone (TSH). No toxicologically meaningful differences were observed between the control and AP-treated groups with respect to survival, clinical observations, body weights, food consumption, water consumption, ophthalmology, hematology, clinical chemistry, estrous cycling, sperm parameters, or bone marrow micronucleus formation. A target organ effect was produced by AP in the thyroids of male and female rats at the 10 mg/kg/day level after 14 and 90 days of exposure. The effect was characterized by significantly increased thyroid weights and thyroid histopathology consisting primarily of follicular cell hypertrophy with microfollicle formation and colloid depletion. These changes were reversible after a nontreatment recovery period of 30 days. Statistically significant changes in TSH and thyroid hormones were observed at all AP dosage levels tested; however, no thyroid organ weight or histopathological effects were observed at AP dosage levels < or = 1.0 mg/kg/day. In the absence of thyroid organ weight and histopathological effects, the toxicological significance of TSH and thyroid hormone changes at AP dosage levels < or = 1.0 mg/kg/day remains to be determined.     

Protective effect of -arginine against nephrotoxicity induced by cyclosporine in normal rats

Effects of L-arginine (L-arg) and aminoguanidine (AG) on the nephrotoxicity induced by cyclosporine (CsA) were investigated. After injection of CsA (15 mg kg(-1) day (-1)i.p. for 10 days), it induced nephrotoxicity, manifested biochemically by a significant elevation of serum urea and creatinine. In addition, a marked increase in lipid peroxides measured as malondialdehyde (MDA) as well as a significant decrease in glutathione peroxidase (GSH-Px) activity (EC.1.11.1.9) and reduced glutathione content (GSH) in kidney tissues homogenate were observed. Nephrotoxicity was further confirmed by histopathological investigation. Oral administration of L-arg (300 mg kg (-1)day(-1) orally) for 5 days before and 10 days concomitant with CsA injection produced a significant protection against nephrotoxity induced by CsA. The amelioration of nephrotoxicity was evidenced by significant reductions in serum urea and creatinine concentrations. In addition, L-arg prevented the rise of MDA as well as reduction of GSH-Px activity and reduced GSH content in kidney tissue. The protective effects of L-arg against CsA-induced nephrotoxicity were further confirmed by histopathological examination. However, oral supplementation of AG (100 mg kg (-1)day(-1) p.o.) did not protect the kidney from the damaging effects of CsA. These results suggest that L-arg can ameliorate kidney dysfunction induced by CsA via a mechanism(s) which involves the production of nitric oxide. In addition, L-arg may therefore be a beneficial remedy for CsA nephrotoxicity and can be used to improve the therapeutic index of CsA.     

Possible protective effect of melatonin and/or desferrioxamine against streptozotocin-induced hyperglycaemia in mice.

There is a clear link between diabetes and oxidative stress. Hyperglycaemia leads to free radical generation and alteration of endogenous antioxidants. The present study is an attempt to evaluate the possible protective effect of melatonin (MLT) and/or desferrioxamine (DF) against streptozotocin (STZ)-induced hyperglycaemia in mice. Serum lipid profile, pancreatic tissue contents of glutathione (GSH) and malondialdehyde (MDA) were determined. MLT and/or DF were given p.o. in doses of 5 mg kg(-1)day(-1)and 250 mg kg(-1) day(-1), respectively for 15 consecutive days prior to STZ treatment (60 mg kg(-1) day(-1) i.p.) for 3 consecutive days. Results revealed that STZ induced a marked increase in serum glucose, serum triglycerides (TG), cholesterol (CHO) and LDL-cholesterol. On the contrary HDL-cholesterol was markedly decreased in STZ-treated group. Moreover, STZ induced a significant decrease in the pancreatic content of GSH with concomitant increase in MDA content. Administration of MLT or (MLT+DF) prior to STZ treatment revealed a marked decrease in serum glucose level by 35.6 and 31.6%, respectively as compared to STZ-treated group. Furthermore, MLT pretreatment of STZ-induced hyperglycemic mice, has not only normalized GSH content of pancreatic tissues but also increased its level more than that of control animals by 110%. On the contrary, MDA content of pancreatic tissues was markedly decreased even lower than normal control group. MLT also, induced a marked protection in terms of decreasing serum CHO, LDL, TG by 21.8, 83.8 and 82.2%, respectively, while HDL was increase by 56% as compared to STZ treated group. DF was found to be less effective than MLT in the protection against STZ-induced hyperglycemia. In conclusion, these data suggest that MLT protects against the damaging consequences induced by hyperglycemia either systemically or in the pancreatic tissues.     

Cisplatin-induced cardiotoxicity: Mechanisms and cardioprotective strategies

Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity that limits the clinical use of cisplatin as an anti-tumoral drug. Our study was conducted to evaluate the protective potential of acetyl-l-carnitine, DL-α-lipoic acid and silymarin against cisplatin-induced myocardial injury. Eighty male albino rats were divided into eight groups. The first four groups were treated with normal saline, acetyl-l-carnitine (500 mg/kg, i.p.), DL-α-lipoic acid (100 mg/kg, p.o.) and silymarin (100 mg/kg, p.o.) respectively, for 10 successive days. The remaining groups were treated with the same doses of normal saline, acetyl-l-carnitine, DL-α-lipoic acid and silymarin, respectively, for 5 successive days before and after a single dose of cisplatin (10 mg/kg, i.p.). Serum activities of lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB) and plasma cardiac troponin I (cTnI) concentration were estimated. Malondialdehyde (MDA), reduced glutathione (GSH) contents, superoxide dismutase activity (SOD) and protein content in cardiac tissues were measured. Moreover, integrity of both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) was also examined. Cisplatin-treated rats experienced a significant elevation of serum activities of LDH, CK, CK-MB and cTnI plasma concentration. These effects were accompanied by a significant increase in MDA level. On the other hand, a significant decrease in GSH content, SOD activity and total protein content was observed. In addition, both mtDNA and nDNA were heavily damaged. However, acetyl-l-carnitine, DL-α-lipoic acid and silymarin significantly attenuated the cisplatin-evoked disturbances in the above-mentioned parameters. In conclusion, the former drugs were proven to be potential candidates to ameliorate cisplatin-induced cardiotoxicity.