Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats.
Methotrexate (MTX), a chemotherapeutic and immunosuppressant drug, is generally well-tolerated by most patients. However, its cytotoxic nature contributes to life-threatening side effects including hepatotoxicity and nephrotoxicity. The present study investigated the possible role of tumor necrosis factor-alpha (TNF-α) inhibitor, etanercept and inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine, on MTX-induced hepatotoxicity and nephrotoxicity in rats. Rats were divided into 7 groups: control group, etanercept group, aminoguanidine group, MTX group, MTX+etanercept group, MTX+aminoguanidine group, and MTX+etanercept+aminoguanidine group. MTX caused hepatotoxicity and nephrotoxicity as evidenced biochemically by significant increase in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and creatinine, respectively as well as by histopathological changes. Such effects were associated with significant changes in oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), catalase, and glutathione (GSH)) as well as by upregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. Etanercept and aminoguanidine significantly attenuated MTX-hepatotoxicity and nephrotoxicity. The protective effect of either agent was associated with significant improvement in oxidative stress parameters as well as by downregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. The study suggested that inhibitors of either TNF-α and/or iNOS have protective effect in MTX-induced hepatotoxicity and nephrotoxicity. The protective effect of either agent relies, at least partially, on their antioxidant effects and decreased TNF-α, iNOS, and caspase-3 expressions.
Department of Pharmacology, Faculty of Medicine, Minia University, Egypt.
Heba M
HM
Hafez
Department of Pharmacology, Faculty of Medicine, Minia University, Egypt. Electronic address: maim69@yahoo.com.
Mohamed A
MA
Ibrahim
Department of Pharmacology, Faculty of Medicine, Minia University, Egypt.
Salwa A
SA
Ibrahim
Department of Pharmacology, Faculty of Medicine, Minia University, Egypt.
Entesar F
EF
Amin
Department of Pathology, Faculty of Medicine, Minia University, Egypt.
Wafaey
W
Goma
Department of Pharmacology, Faculty of Medicine, Minia University, Egypt.
Aly M
AM
Abdelrahman
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D000068800:Etanercept / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015415:Biomarkers; D006146:Guanidines; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3; D000068800:Etanercept; C004479:pimagedine; D008727:Methotrexate
Aminoguanidine; Etanercept; Hepatotoxicity; Methotrexate; Nephrotoxicity