ABSTRACT
Cilostazol and verapamil are widely used cardiovascular drugs, explored a beneficial effect on different organs-induced toxicities. We investigated whether the Nrf2 (nuclear erythroid factor 2) and its downstream pathway are involved in the protective role of these drugs against TAA-induced renal damage. Renal biomarkers (creatinine and urea) and histopathology were observed. Antioxidant and oxidant indicators; superoxide dismutase (SOD), reduced glutathione (GSH), malondialdehyde (MDA) and total nitrite (NO) were also measured. Antioxidant markers like; Nrf2/hemoxegenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions were determined by ELISA and immunohistochemistry. Cilostazol and verapamil pretreatment improved serum creatinine and urea elevation. Examined drugs also have an ameliorative effect on TAA-induced elevation in MDA and NO activities and antioxidant enzymes; SOD and GSH. Additionally, the pretreated drugs significantly up-regulated Nrf2/HO-1/NQO-1 expression levels. In conclusion, cilostazol and verapamil exerted their protective effects partially via a Nrf2/HO-1/NQO-1 activation pathway with anti-oxidant roles.
Subject(s)
Antioxidants/pharmacology , Cilostazol/pharmacology , Heme Oxygenase (Decyclizing)/metabolism , Kidney Diseases/prevention & control , Kidney/drug effects , NAD(P)H Dehydrogenase (Quinone)/metabolism , NF-E2-Related Factor 2/metabolism , Thioacetamide , Verapamil/pharmacology , Animals , Cytoprotection , Disease Models, Animal , Kidney/enzymology , Kidney/pathology , Kidney/physiopathology , Kidney Diseases/chemically induced , Kidney Diseases/enzymology , Kidney Diseases/pathology , Male , Oxidative Stress/drug effects , Rats , Signal Transduction/drug effectsABSTRACT
AIMS: Hydrogen sulfide (H(2)S), an endogenous gaseous mediator, plays an important role in regulation of many physiological and pathological processes. On the other hand, acetaminophen overdose is a major cause of drug-induced liver failure. The aim of this study therefore is to evaluate the possible curative effects of H(2)S against acetaminophen-induced hepatotoxicity. MAIN METHODS: Male Swiss mice were treated with sodium hydrogen sulfide, a H(2)S donor, 30 min after acetaminophen administration. N-acetylcysteine, a therapeutic antidote, was used as a reference drug. KEY FINDINGS: H(2)S treatment resulted in hepatocurative effects as evident by a significant decrease in serum alanine aminotransferase and hepatic malondialdehyde and nitric oxide levels, with a concurrent increase in hepatic glutathione content compared to acetaminophen-treated group. H(2)S did not alter catalase activity. Additionally, immunohistochemical analysis demonstrated that H(2)S treatment markedly reduced tumor necrosis factor-α expression, while expression of cyclooxygenase-2 was markedly enhanced with nuclear localization into hepatocytes. The curative effects of H(2)S were confirmed by liver histopathological examination and were maintained in the presence of glibenclamide, an antagonist of ATP-sensitive potassium (K(ATP)) channels. SIGNIFICANCE: H(2)S treatment markedly alleviates acetaminophen hepatotoxicity in mice possibly, in part, through anti-oxidative and anti-inflammatory effects but not likely to be coupled with activation of K(ATP) channels. The hepatocurative effects of H(2)S are comparable to N-acetylcysteine. Hence, H(2)S has a potential therapeutic value for treatment of acetaminophen hepatotoxicity.
