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979208 
Journal Article 
Alpha-lipoic acid and quercetin protect against methotrexate induced-hepatotoxicity in rats 
Darwish, HA; Mahdy, A 
2009 
Yes 
HealthMED
ISSN: 1840-2291 
3 
1 
80-89 
English 
WOS:000264655800014 
Background: Methotrexate (MTX), a folic acid antagonist, is widely used as cytotoxic chemotherapeutic agent for malignanoies as well as in the treatment of various inflammatory diseases. The efficacy of this agent is often limited by severe side effects and toxic conditions. Regarding the mechanism of these side effects, several hypotheses have been put forward, among which oxidative stress is noticeable. Aims & Objectives: The present study was undertaken to determine whether alpha-lipoic acid or quercetin, potent free radical scavengers, could ameliorate MTX-induced oxidative liver injury and modulate immune response. The study also aimed to investigate the possible role of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of MTX-induced hepatoxicity. Study design/Methods: Rats were randomly divided into four experimental groups beside a normal control group consisting each of 8 animals. Following a single injection of MTX (20 mg/kg; i.p), experimental groups were allowed to receive either alpha-lipoic acid (50 mg/kg/day; orally), quercetin (10 mg/kg/day; i.p in dimethylsulphoxide (DMSO)) or the vehicle DMSO alone. Treatment was carried out for 5 consecutive days. On the sixth day, blood serum was separated and used for the determination of TNF-alpha level as well aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and alanine aminotransferase (ALT) activities to assess the hepatic function. Liver tissue samples were collected for the estimation of tissue malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NO) levels, myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT) activities as well as for histological examination. Results obtained were statistically analysed by one way analysis of variance (ANOVA) followed by Tukey-Kramer multiple comparison test. Significance was considered at p<0.05. Findings: MTX caused a significant reduction in hepatic GSH level, SOD and CAT activities while MDA and MPO activities were significantly increased. Hepatic NO as well sa serum TNF-alpha levels were markedly elevated following MTX treatment. Only ALT rather than AST activity was significantly reversed by either alpha-lipoic acid or quercetin treatment. Similarly, histological analysis revealed that both treatments were effective in attenuating tissue damage. However, the effect alpha-lipoic acid was more pronounced. Conclusion: The study indicates that oxidative stress, NO as well as TNF-alpha may play an important role in the pathogenesis of MTX-induced hepatoxicity. alpha-Lipoic acid and quercetin have protective aspects in this process through their antioxidant and anti-inflammatory effects. These data imply that antioxidant therapy may be of therapeutic potential in alleviating hepatotoxicity in patients receiving MTX treatment. 
methotrexate; alpha-Lipoic acid; quercetin; nitric oxide; TNF-alpha; oxidative stress