Assessment of d-methionine protecting cisplatin-induced otolith toxicity by vestibular-evoked myogenic potential tests, ATPase activities and oxidative state in guinea pigs

• Vestibular-evoked myogenic potential (VEMP) tests can assess otolith toxicity.
• Ocular VEMP amplitudes were significantly decreased after cisplatin exposure.
• Cisplatin administration caused decreased ATPase activities in otolith organs.
• Oxidative stress of otolith organs was increased after cisplatin treatment.
• d-Met attenuated cisplatin-induced otolith toxicity in guinea pigs.

To date, inadequate study has been devoted to the toxic vestibular effects caused by cisplatin. In addition, no electrophysiological examination has been conducted to assess cisplatin-induced otolith toxicity. The purposes of this study are thus two-fold: 1) to determine whether cervical vestibular-evoked myogenic potentials (VEMPs) and ocular VEMPs are practical electrophysiological methods of testing for cisplatin-induced otolith toxicity and 2) to examine if d-methionine (d-met) pre-injection would protect the otolith organs against cisplatin-induced changes in enzyme activities and/or oxidative status. Guinea pigs were intraperitoneally treated once daily with the following injections for seven consecutive days: sterile 0.9% saline control, cisplatin (5 mg/kg) only, d-met (300 mg/kg) only, or a combination of d-met (300 mg/kg) and cisplatin (5 mg/kg), respectively, with a 30 minute window in between. Each animal underwent the oVEMP and cVEMP tests before and after treatment. The changes in the biochemistry of the otolith organs, including membranous Na+, K+-ATPase and Ca2 +-ATPase, lipid peroxidation (LPO) levels and nitric oxide (NO) levels, were also evaluated. In the cisplatin-only treated guinea pigs, the mean amplitudes of the oVEMP tests were significantly (p < 0.05) decreased when compared to the other three groups. In guinea pigs receiving both d-met and cisplatin, the amplitudes of their oVEMP tests were significantly larger (p < 0.05) than those of the cisplatin-only group, but smaller (p < 0.05) than those of the saline control or d-met-only group. However, no significant difference of the amplitudes of cVEMP tests was noted among the four groups. In comparison with the other three groups, the cisplatin-only group had the lowest (ps < 0.05) mean Na+, K+-ATPase and Ca2 +-ATPase, and the highest (ps < 0.05) LPO and NO levels. The oVEMP tests were feasible for the evaluation of cisplatin-related otolith dysfunction. d-Met attenuated the reduced ATPase activities and increased oxidative stress induced by cisplatin toxicity in the otolith organs.