Ameliorative effect of flunarizine in cisplatin-induced acute renal failure via mitochondrial permeability transition pore inactivation in rats.
This study was aimed to evaluate the protective effect of flunarizine on cisplatin-induced acute renal failure. Administration of cisplatin (6 mg/kg, i.p. on day 6) significantly increased serum blood urea nitrogen and creatinine, urinary N-acetyl β-D-glucosaminidase, tissue thiobarbituric acid reactive substances and total calcium whereas, decreased body weight, fractional excretion of sodium, creatinine clearance tissue-reduced glutathione, mitochondrial cytochrome c oxidase, and ATP levels were observed in acute renal failure rats. Moreover, cisplatin produced histopathological changes in the renal tissue. Furthermore, flunarizine (100, 200, and 300 μM/kg, p.o., for six consecutive days) was administered to evaluate its therapeutic potential in acute renal failure, and the results were compared with cyclosporin A (50 μM/kg, p.o., for six consecutive days) as a reference drug. Flunarizine resulted in the attenuation of cisplatin-induced renal dysfunction, oxidative stress marker, mitochondrial damage, and histopathological changes in rats. Medium and higher doses of flunarizine produced significant renal protective effect which was comparable to cyclosporin A. The results of this study clearly revealed that flunarizine protected the kidney against the nephrotoxic effect of cisplatin via mitochondrial permeability transition pore inactivation potential.
Rayat Institute of Pharmacy, Ropar Campus, Nawanshahr District, Near Railmajra, Ropar, 144533 Punjab, India. arunachalammu@gmail.com
Arunachalam
A
Muthuraman
Shailja
S
Sood
Sumeet Kumar
SK
Singla
Ajay
A
Rana
Atinderjeet
A
Singh
Amandeep
A
Singh
Jai
J
Singh
D000118:Acetylglucosaminidase / Q000652:urine; D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D003404:Creatinine / Q000097:blood / Q000652:urine; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D005444:Flunarizine / Q000494:pharmacology / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017392:Thiobarbituric Acid Reactive Substances; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D012964:Sodium; D003404:Creatinine; D003576:Electron Transport Complex IV; D000118:Acetylglucosaminidase; D005978:Glutathione; D002945:Cisplatin; D005444:Flunarizine; D002118:Calcium