Luteolin ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of platinum accumulation, inflammation and apoptosis in the kidney

• Published in: Toxicology (Amsterdam) Vol. 310; pp. 115 - 123
• Main Authors: Domitrović, Robert, Cvijanović, Olga, Pugel, Ester Pernjak, Zagorac, Gordana Blagojević, Mahmutefendić, Hana, Škoda, Marko
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 09-08-2013
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - toxicity; Apoptosis; Apoptosis - drug effects; Biomarkers - blood; blood serum; Blotting, Western; caspase-3; cisplatin; Cisplatin - pharmacokinetics; Cisplatin - toxicity; Cisplatin nephrotoxicity; creatinine; cytochrome P-450; Dose-Response Relationship, Drug; Drug Administration Schedule; Emergency; glutathione; Immunohistochemistry; Inflammation; Kidney - drug effects; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Kidney Diseases - chemically induced; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidney Diseases - prevention & control; Kidney Function Tests; kidneys; Luteolin; Luteolin - administration & dosage; Luteolin - pharmacology; Luteolin - therapeutic use; Male; Mice; Mice, Inbred BALB C; nephroprotective effect; nephrotoxicity; Oxidative Stress - drug effects; Oxidative/nitrosative stress; platinum; Platinum - metabolism; prostaglandin synthase; toxicology; transcription factor NF-kappa B; tumor necrosis factor-alpha; urea nitrogen; Inflammation; Luteolin; Cisplatin nephrotoxicity; Oxidative/nitrosative stress; Apoptosis
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2013.05.015

The aim of this study was to investigate the effects of flavone luteolin against cisplatin (CP)-induced kidney injury in mice. Luteolin at doses of 10mg/kg was administered intraperitoneally (ip) once daily for 3 days following single CP (10 or 20mg/kg) ip injection. Mice were sacrificed 24h after the last dose of luteolin. The CP treatment significantly increased serum creatinine and blood urea nitrogen and induced pathohistological changes in the kidneys. Renal oxidative/nitrosative stress was evidenced by decreased glutathione (GSH) levels and increased 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) formation as well as cytochrome P450 2E1 (CYP2E1) expression. The CP administration triggered inflammatory response in mice kidneys through activation of nuclear factor-kappaB (NF-κB) and overexpression of tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2). Simultaneously, the increase in renal p53 and caspase-3 expression indicated apoptosis of tubular cells. The administration of luteolin significantly reduced histological and biochemical changes induced by CP, decreased platinum (Pt) levels and suppressed oxidative/nitrosative stress, inflammation and apoptosis in the kidneys. These results suggest that luteolin is an effective nephroprotective agent, with potential to reduce Pt accumulation in the kidneys and ameliorate CP-induced nephrotoxicity.