DIFFERENTIAL DAMAGE TO AUDITORY NEURONS AND HAIR-CELLS BY OTOTOXINS AND NEUROPROTECTION BY SPECIFIC NEUROTROPHINS IN RAT COCHLEAR ORGANOTYPIC CULTURES

Therapeutic ototoxic drugs are one of the major causes of damage in th e peripheral auditory system, leading to hearing loss. In this study, we have examined the toxic actions of three classes of ototoxins (sodi um salicylate, gentamicin and cisplatin) in organotypic cultures of po stnatal cochlear explants. In these cultures, afferent innervation of hair cells by primary auditory neurons remained intact. Double labelli ng with a monoclonal antibody against neurofilament protein and a phal loidin-fluorescein isothiocyanate conjugate revealed that the three ty pes of drugs induced differential damage to auditory neurons and hair cells in the cochlea. While gentamicin preferentially caused hair cell death, sodium salicylate specifically induced degeneration of auditor y neurons. In contrast, cisplatin resulted in destruction of both audi tory neurons and hair cells, Neuronal degeneration was largely prevent ed by the addition of neurotrophin-4/5, brain-derived neurotrophic fac tor and neurotrophin-3 to the culture media together with the ototoxin s, while nerve growth factor and other growth factors had no effect. I n contrast, the hair cell loss caused by cisplatin or gentamicin was n ot attenuated by the presence of neurotrophins. These results suggest that ototoxic mechanisms Of salicylates, aminoglycosides and chemother apeutic agents are different. Auditory neuronal loss induced by ototox ins may be prevented by specific neurotrophins.