Nephrotoxicity is the major dose-limiting factor of
cisplatin chemotherapy.
Reactive oxygen species generated in mitochondria are thought to be the main cause of cellular damage in such injury. The present study examined, in vivo, the protective potential of the
hydroxyl radical scavenger
dimethylthiourea (
DMTU) against
cisplatin-induced effects on renal mitochondrial bioenergetics, redox state and oxidative stress. Adult male Wistar rats (200 to 220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of
saline solution (1 ml/100 g
body weight). The second group was given only
DMTU (500 mg/kg
body weight, i.p, followed by 125 mg/Kg, i.p., twice a day until they were killed). The third group was given a single injection of
cisplatin (10 mg/kg
body weight, i.p.). The fourth group was given
DMTU (500 mg/kg
body weight, i.p.), just before the
cisplatin injection (10 mg/kg
body weight, i.p.), followed by
injections of
DMTU (125 mg/kg
body weight, i.p.) twice a day until they were killed. Animals were killed 72 h after the treatment. Besides not presenting any direct effect on mitochondria,
DMTU substantially inhibited
cisplatin-induced mitochondrial injury and cellular death by apoptosis, suppressing the occurrence of
acute renal failure. All the following
cisplatin-induced effects were prevented by
DMTU: (1) increased plasmatic levels of
creatinine and blood
urea nitrogen (BUN); (2) decreased
ATP content,
calcium uptake and electrochemical potential; (3) oxidation of
lipids, including
cardiolipin; and oxidation of
proteins, including sulfhydryl, and
aconitase enzyme, as well as accumulation of carbonyl
proteins; (4) depletion of the
antioxidant defense (
NADPH and GSH) and (5) increased activity of the apoptosis executioner
caspase-3. Our findings show the important role played by mitochondria and
hydroxyl radicals in
cisplatin-induced nephrotoxicity, as well as the effectiveness of
DMTU in preventing the renal mitochondrial damage caused by
cisplatin. These results strongly suggest that protection of mitochondria by
hydroxyl radical scavengers may be an interesting approach to prevent the kidney tissue damage caused by
cisplatin-
chemotherapy.