Carboplatin-induced oxidative stress in rat cochlea.
Carboplatin is currently being used in the clinic against a variety of human cancers. However, high dose carboplatin chemotherapy resulted in ototoxicity in cancer patients. This is the first study to show carboplatin-induced oxidative stress response in the cochlea of rat. Male Wistar rats were divided into two groups of six animals each and treated as follows: (1) control (normal saline, i.p.) and (2) carboplatin (256 mg/kg, i.p.). Animals in both groups were sedated with ketamine/xylazine and auditory brainstem-evoked responses were recorded before and 4 days after treatments. The animals were sacrificed on the fourth day and cochleae were harvested and analyzed. A significant elevation of the hearing threshold shifts was noted at clicks, 8, 16, and 32 kHz tone burst stimuli following carboplatin administration. Carboplatin significantly increased nitric oxide and malondialdehyde levels, xanthine oxidase and manganese-superoxide dismutase activities in the cochlea indicating enhanced flux of free radicals. Cochlear glutathione levels, antioxidant enzyme activities such as copper zinc-superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase and enzyme protein levels were significantly depleted 4 days after carboplatin treatment. The data suggest that carboplatin induced free radical generation and antioxidant depletion, and caused oxidative injury in the cochleae of rats.
Husain
K
K
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, 62794-9629, USA. khusain@siumed.edu
Whitworth
C
C
Somani
S M
SM
Rybak
L P
LP
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism; D001309:Auditory Threshold / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage / Q000633:toxicity*; D002374:Catalase / Q000037:antagonists & inhibitors; D003051:Cochlea / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism* / Q000503:physiopathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism
D000970:Antineoplastic Agents; D000975:Antioxidants; D005609:Free Radicals; D009569:Nitric Oxide; D008315:Malondialdehyde; D016190:Carboplatin; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione