A novel free radical scavenger, edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo.
Accumulating evidence suggests that enhanced peroxidative damage caused by reactive oxygen species (ROS) may contribute to the pathogenesis of cisplatin-induced acute renal failure. Nevertheless, little is known about the involvement of oxygen radicals in cisplatin nephropathy. In this study, we investigated the effects of a novel free radical scavenger, 3-methyl-1-phenyl-pyrazolin-5-one (MCI-186; edarabone), on murine proximal tubular cell (PTC) damage induced by exposure to cisplatin in vitro and on renal function in an in vivo model of cisplatin-induced acute renal failure. Edarabone inhibited cisplatin-induced (40 microM, 24 h) cytotoxicity in a concentration-dependent manner (10-5 to 10-3 M). Edarabone also attenuated cisplatin-induced mitochondrial transmembrane potential loss and ROS production of PTCs. In the in vivo study, male Wistar rats were cotreated with cisplatin (5 mg/kg, i.p.) and edarabone (1 or 5 mg/kg, i.v.). Effects of edarabone on the kidney were examined 5 days after treatment. Cisplatin resulted in renal dysfunction, renal tubular damage, mitochondrial damage (assayed by histochemical staining for respiratory chain complex IV), renal protein oxidation (examined by Western blot analysis using a specific antibody for carbonyl group-containing proteins), and tubular apoptosis (determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining). The above changes were attenuated by edarabone treatment. Thus, edarabone exhibited cytoprotective effects in PTCs and renoprotective effects against cisplatin. Our findings suggest that ROS, in particular hydroxyl radicals, are involved in cisplatin nephropathy and that edarabone may be potentially useful in protecting the kidneys and prevention of acute renal failure.
Satoh
Minoru
M
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. satoh-minoru@mx1.tiki.ne.jp
Kashihara
Naoki
N
Fujimoto
Sohachi
S
Horike
Hideyuki
H
Tokura
Takehiko
T
Namikoshi
Tamehachi
T
Sasaki
Tamaki
T
Makino
Hirofumi
H
D000208:Acute Disease; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000494:pharmacology*; D017209:Apoptosis; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D007677:Kidney Function Tests; D050356:Lipid Metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009696:Nucleic Acids / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D016166:Free Radical Scavengers; D009696:Nucleic Acids; D017382:Reactive Oxygen Species; D002945:Cisplatin; D000077553:Edaravone; D000983:Antipyrine