Correlation of increased activities of Na+, K+-ATPase and Ca2+-ATPase with the reversal of cisplatin ototoxicity induced by d-methionine in guinea pigs

Na+, K+-ATPase and Ca2+-ATPase in the cochlear lateral wall play an important role in maintaining ionic homeostasis and physiologic function of the cochlea. The present study was designed to test whether the changes of Na+, K+-ATPase and Ca2+-ATPase activities of the cochlear lateral wall and the brainstem of guinea pigs after receiving cisplatin for seven consecutive days were correlated with the altered auditory brainstem responses (ABR). Furthermore, whether a chemoprotective agent, d-methionine reversed the increased ABR threshold induced by cisplatin accompanied with the increased ATPase activities was also evaluated. The results obtained showed that cisplatin exposure caused not only a significant increase of threshold but also altered various absolute wave and interwave latencies of ABR. In addition, cisplatin significantly decreased the Na+, K+-ATPase and Ca2+-ATPase activities in the cochlear lateral wall with a good dose-response relationship. Regression analysis indicated that an increase of ABR threshold was well correlated with a decrease of both Na+, K+-ATPase and Ca2+-ATPase activities in the cochlear lateral wall. A chemoprotectant, d-methionine indeed reversed both abnormalities of ABR and ATPase activities in a well correlation function. The selectivity of these observed changes induced by cisplatin and d-methionine was revealed by the findings that cisplatin-treated guinea pigs had normal III-V interwave latency of ABR and no reduction of Na+, K+-ATPase and Ca2+-ATPase specific activities in the brainstem, which is in accordance with the nonpenetrable cisplatin across the blood brain barrier. Taken all together, the present findings suggest that biochemical damage and ionic disturbance may contribute to cisplatin-induced ototoxicity to some extent, which can be reversed by d-methionine.