Hepato- and neurotoxicity induced by thioacetamide: Protective effects of melatonin and dimethylsulfoxide

Túnez, Isaac; Muñoz, M. C.; Villavicencio, Michelle A.; Medina, F; Prado, Estíbaliz Pérez de; Espejo, Isabel; Barcos, Montserrat; Salcedo, Manuel; Feijóo, Montserrat; Montilla, Pedro

doi:10.1016/j.phrs.2005.03.007

Cited by 52 publications

(42 citation statements)

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“…5,6 Its binding to tissue macromolecules might induce hepatic necrosis and oxidative stress. 7,8 Oxidative stress may sustain liver fibrosis progression by the activation and morphological change in hepatic stellate cells (HSCs) that include promoting proliferative activity, synthesis and degradation/remodeling of the extracellular matrix (ECM), chemotaxis and proinflammatory activity. 9,10 In the fibrotic liver, an imbalance takes place between excess synthesis and/or a decrease in the removal of ECM with consequent scarring.…”

Section: Introductionmentioning

confidence: 99%

Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

et al. 2006

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Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. a-Melanocyte-stimulating hormone (a-MSH) is a 13-amino-acid peptide with potent anti-inflammatory effects. We have previously demonstrated that a-MSH gene therapy protects against thioacetamide (TAA)-induced acute liver failure. Therefore, the aim of this study is to investigate whether a-MSH gene therapy possesses antihepatic fibrogenic effect. Liver fibrosis was induced by long-term TAA administration in mice. a-Melanocyte-stimulating hormone expression plasmid was delivered via electroporation after liver fibrosis was established. Our results showed that a-MSH gene therapy attenuated liver fibrosis in TAA-treated mice. Reverse transcription polymerase chain reaction revealed that a-MSH gene therapy attenuated the liver transforming growth factor-b1, collagen a1 and cell adhesion molecule mRNA upregulation. Following gene transfer, the expression of a-smooth muscle actin and cyclooxygenase-2 were both significantly attenuated. Further, a-MSH significantly increased matrix metalloproteinase (MMP), while tissue inhibitors of matrix metalloproteinase (TIMPs) were inactivated. In summary, a-MSH gene therapy reversed established liver fibrosis in mice and prevented the upregulated fibrogenic and pro-inflammatory gene responses after TAA administration. Its collagenolytic effect might be attributed to MMP and TIMP modulation. Hence, a-MSH gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

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Section: Introductionmentioning

confidence: 99%

Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

et al. 2006

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“…This research found that melatonin and DMSO, although melatonin more significantly, decreased the intensity of the changes produced by the administration of TAA alone. 21 Furthermore, melatonin either alone or combined with TAA increased the blood urea nitrogen (BUN) levels and decreased the ammonia values compared with control animals. 21 In the current study, we examined and compared the protective effects of melatonin, vitamin E and L-carnitine on brain and liver oxidative stress and on the liver damage induced by TAA.…”

Section: Introductionmentioning

confidence: 99%

Comparison of melatonin, vitamin E and L‐carnitine in the treatment of neuro‐ and hepatotoxicity induced by thioacetamide

Túnez

Muñoz

Medina

et al. 2005

Cell Biochemistry & Function

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This study was designed to evaluate and compare the effect of melatonin, vitamin E and L-carnitine on brain and liver oxidative stress and liver damage. Oxidative stress and hepatic failure were produced by a single dose of thioacetamide (TAA) (150 mg kg(-1)) in Wistar rats. A dose of either melatonin (3 mg kg(-1)) vitamin E (20 mg kg(-1) ) or L-carnitine (100 mg kg(-1)) was used. Blood samples were taken from the neck vasculature in order to determine ammonium, blood urea nitrogen (BUN) and liver enzymes. Lipid peroxidation products, glutathione (GSH) content and antioxidative enzymes were determined in cerebral and hepatic homogenates. The results showed a decrease in BUN and in the antioxidant enzymes activities and GSH in the brain and liver. Likewise, TAA induced significant enhancement of lipid peroxidation products levels in both liver and brain, as well as in ammonia values. Melatonin, vitamin E and L-carnitine, although melatonin more significantly, decreased the intensity of the changes produced by the administration of TAA alone. Furthermore melatonin combined with TAA, decreased the ammonia levels and increased the BUN values compared with TAA animals. Also it was more effective than vitamin E or L-carnitine in these actions. These data show the protective effect of these agents, especially melatonin, against oxidative stress and hepatic damage present in fulminant hepatic failure.

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“…To survey the antioxidative effect of food factors, it is necessary to investigate effects of a known antioxidant on the liver. Only limited studies are available and DMSO is reported to function as an antioxidant in cultured hepatocytes ( 6 ) as well as in the rat liver under thioacetamide intoxication (6)(7)(8). In this report, we have attempted to investigate whether DMSO functions in vivo as an antioxidant and protects against necrosis of the liver caused by D -Galn even in a pharmacological dose.…”

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confidence: 99%

Inhibitory Effect of Dimethyl Sulfoxide (DMSO) on Necrosis and Oxidative Stress Caused by D-Galactosamine in the Rat Liver

Iida

Fujii

Koga

et al. 2007

J Nutr Sci Vitaminol

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Summary D -Galactosamine ( D -Galn: 300 mg/kg) was intraperitoneally administered to rats. After 6 h the activity of plasma GOT and GPT was significantly higher than that of the control group and plasma GOT and GPT activities increased thereafter. These results indicated that the necrotic process was initiated at about 6 h and developed thereafter. With coadministration of DMSO (1 h before administration of D -Galn: 2.5 mL/kg, oral), plasma GOT and GPT were significantly lower, showing that DMSO inhibited the necrotic action of DGaln. After 6-24 h of D -Galn administration, the hepatic level of vitamin C, the most sensitive indicator of oxidative stress, decreased significantly, indicating that oxidative stress was significantly enhanced 6 h after D -Galn intoxication and thereafter. DMSO significantly restored the liver vitamin C level 24 h after D -Galn injection, demonstrating that DMSO effectively ameliorated the oxidative stress caused by D -Galn, resulting in the prevention of necrosis of the liver. Phosphorylated JNK and phospho-ERK were significantly increased transiently 6-12 h after treatment with D -Galn. These results indicated that oxidative stress and the activation of JNK took place almost simultaneously. Phosphorylated p38 MAPK was not changed and DMSO treatment did not affect the change of these MAPKs by D -Galn. Key Words DMSO, galactosamine, MAPK, oxidative stress, vitamin C Hepatoprotection remains one of the major challenges in nutritional and clinical therapy to limit liver injuries such as chronic hepatitis and fulminant hepatic failure. To study this issue more effectively, experimental methods are necessary to cause effective hepatic failure. Chemical toxins such as D -galactosamine ( D -Galn) ( 1 ), thioacetamide ( 2 ), and carbon tetrachloride ( 3 ) have been used for this purpose. D -Galn is known as a toxin causing necrosis of the liver by UTP depletion and inhibition of protein synthesis ( 4 ). Recently, we reported that radical reactions were caused by D -Galn in the early stage based on a decrease in vitamin C ( 1 ), resulting in necrosis. In chemically induced hepatitis ( 1-3 ), liver vitamin C was firstly consumed by oxidative stress, indicating that vitamin C was the most sensitive indicator of oxidative stress ( 5 ).Antioxidants in foods are therefore expected to protect the liver from oxidative stress caused by these chemicals. To survey the antioxidative effect of food factors, it is necessary to investigate effects of a known antioxidant on the liver. Only limited studies are available and DMSO is reported to function as an antioxidant in cultured hepatocytes ( 6 ) as well as in the rat liver under thioacetamide intoxication (6)(7)(8). In this report, we have attempted to investigate whether DMSO functions in vivo as an antioxidant and protects against necrosis of the liver caused by D -Galn even in a pharmacological dose. For this purpose we evaluated oxidative stress using hepatic vitamin C level and activation profiles of the three major subclasses of the MAPK (mitogen a...

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Hepato- and neurotoxicity induced by thioacetamide: Protective effects of melatonin and dimethylsulfoxide

Cited by 52 publications

References 34 publications

Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

Comparison of melatonin, vitamin E and L‐carnitine in the treatment of neuro‐ and hepatotoxicity induced by thioacetamide

Inhibitory Effect of Dimethyl Sulfoxide (DMSO) on Necrosis and Oxidative Stress Caused by D-Galactosamine in the Rat Liver

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