UP-REGULATION OF ADENOSINE RECEPTORS IN THE COCHLEA BY CISPLATIN

In a previous study, we have demonstrated the presence of two adenosin e receptor (AR) subtypes, namely A(1) and A(3)AR, in the chinchilla co chlea. One or both of these receptors couple to activation of antioxid ant enzymes, with resulting decreases in lipid peroxidation. The chemo therapeutic agent, cisplatin, was shown to produce ototoxicity within a few days of administration presumably by generating reactive oxygen species (ROS) and :hereby increasing lipid peroxidation. In this study , we focused on whether lipid peroxidation induces hearing loss by ass essing the cochlear antioxidant defense system over a shorter time per iod (24 h) following cisplatin administration. Cisplatin was administe red to anesthetized chinchillas by round window membrane application a nd hearing loss was determined by compound action potential (CAP) and endocochlear potential (EP) 24 and 72 h post-treatment. Elevations in CAP thresholds in response to click and to 2, 4, 8 and 16 kHz tones an d decreases in EP were obtained within 24 h of cisplatin treatment. Th ese changes persisted for at least up to 72 h. Measurements of antioxi dant enzymes indicate no change in the activities of superoxide dismut ase, catalase or glutathione peroxidase, either 24 or 72 h following c isplatin treatment. The levels of malondialdehyde obtained at these ti me points were equivalent to those obtained from the controls. Further more, no difference in cochlear morphology was detectable by scanning electron microscopy at the basal, middle or apical turns of the cochle a within 24 h. By 72 h, however, losses in both inner and outer hair c ells were observed in the basal and middle turns of the cochlea. A maj or finding of this study is that exposure to cisplatin led to a 5-fold up-regulation of [I-125]N-6-2-{4-amino-3-phenyl}ethyladenosine bindin g in the cochlea within 24 h, reflecting increases in expression of AR (s) in this tissue. These data indicate a dissociation between cisplat in acute (within 24 h) ototoxicity and lipid peroxidation. Furthermore , up-regulation of AR(s) may represent a rapid compensatory mechanism by the cochlea to counter the toxic effects of increased ROS generated by cisplatin.