Dose dependent protection by lipoic acid against cisplatin-induced ototoxicity in rats: antioxidant defense system.
This study investigated the alterations that occur in auditory brainstem-evoked responses (ABRs) concurrent with changes in cochlear concentrations of glutathione (GSH), lipid peroxidation, and antioxidant enzyme activity in cisplatin-induced ototoxicity and in dose-dependent otoprotection by an antioxidant lipoate. Male Wistar rats were divided into different groups and were treated as follows, with: (1) vehicle (saline) control; (2) cisplatin (16 mg/kg, i.p.); (3) lipoate (100 mg/kg, i.p.) plus saline; (4) cisplatin plus lipoate (25 mg/kg); (5) cisplatin plus lipoate (50 mg/kg), and (6) cisplatin plus lipoate (100 mg/kg). Post-treatment ABRs were evaluated after three days, the rats were sacrificed, and cochleae were harvested and analyzed. The cisplatin-injected rats showed ABR threshold elevations above the pre-treatment thresholds. Rats treated with lipoate plus cisplatin did not show significant elevation of hearing thresholds. Cisplatin administration resulted in a depletion of cochlear GSH concentration (69% of control), whereas, cisplatin-plus-lipoate treatment increased GSH concentration close to control value. Cisplatin-treated rats showed a decrease in cochlear superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities (57, 78, 59, and 58% of control, respectively), and an increase in malondialdehyde (MDA) concentration (196% of control). Cochlear SOD, CAT, GSH-Px, and GR activities and MDA concentrations were restored in the rats injected with cisplatin plus graded doses of lipoate than those with cisplatin alone. It is concluded that cisplatin-induced ototoxicity is related to impairment of the cochlear antioxidant defense system, and the dose-dependent otoprotection conferred by an antioxidant lipoate against cisplatin ototoxicity is associated with sparing of the cochlear antioxidant defense system.
Rybak
L P
LP
Department of Pharmacology, Southern Illinois University, School of Medicine, Springfield 62794, USA.
Husain
K
K
Whitworth
C
C
Somani
S M
SM
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use*; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects*; D005609:Free Radicals; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D008063:Thioctic Acid / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D000975:Antioxidants; D005609:Free Radicals; D017382:Reactive Oxygen Species; D008063:Thioctic Acid; D002945:Cisplatin