title: Up-regulation of adenosine receptors in the cochlea by cisplatin.
abstract: In a previous study, we have demonstrated the presence of two adenosine receptor (AR) subtypes, namely A1 and A3AR, in the chinchilla cochlea. One or both of these receptors couple to activation of antioxidant enzymes, with resulting decreases in lipid peroxidation. The chemotherapeutic agent, cisplatin, was shown to produce ototoxicity within a few days of administration presumably by generating reactive oxygen species (ROS) and thereby increasing lipid peroxidation. In this study, we focused on whether lipid peroxidation induces hearing loss by assessing the cochlear antioxidant defense system over a shorter time period (24 h) following cisplatin administration. Cisplatin was administered to anesthetized chinchillas by round window membrane application and 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 and decreases in EP were obtained within 24 h of cisplatin treatment. These changes persisted for at least up to 72 h. Measurements of antioxidant enzymes indicate no change in the activities of superoxide dismutase, catalase or glutathione peroxidase, either 24 or 72 h following cisplatin treatment. The levels of malondialdehyde obtained at these time points were equivalent to those obtained from the controls. Furthermore, no difference in cochlear morphology was detectable by scanning electron microscopy at the basal, middle or apical turns of the cochlea within 24 h. By 72 h, however, losses in both inner and outer hair cells were observed in the basal and middle turns of the cochlea. A major finding of this study is that exposure to cisplatin led to a 5-fold up-regulation of [125I]N6-2-[4-amino-3-phenyl]ethyladenosine binding in the cochlea within 24 h, reflecting increases in expression of AR(s) in this tissue. These data indicate a dissociation between cisplatin 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.
authors.affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, Springfield 62794, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Ford
authors.forename: Z
authors.initials: Z
authors.lastname: Nie
authors.forename: C
authors.initials: C
authors.lastname: Whitworth
authors.forename: L P
authors.initials: LP
authors.lastname: Rybak
authors.forename: V
authors.initials: V
authors.lastname: Ramkumar
mesh_terms: D000161:Acoustic Stimulation; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001309:Auditory Threshold / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D002682:Chinchilla; D002945:Cisplatin / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D003055:Cochlear Microphonic Potentials / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000378:metabolism; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced* / Q000503:physiopathology; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000378:metabolism; D012405:Round Window, Ear / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D018047:Receptors, Purinergic P1; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D002945:Cisplatin