Complementary roles of neurotrophin 3 and a N-methyl-D-aspartate antagonist in the protection of noise and aminoglycoside-induced ototoxicity

Recent progress has been made regarding the prevention of hearing loss. How ever, the complete protection of both hair cells and spiral ganglion neuron s, with restored function, has not yet been achieved. It has been shown tha t spiral ganglion neuronal loss can be prevented by neurotrophin 3 (NT3) an d hair cell damage by N-methyl-D-aspartate (NMDA) receptor antagonists. Her e we demonstrate that the combined treatment with MK801. a NMDA antagonist, and NT3 protect both cochlear morphology and physiology from injury. Pretr eatment with MK801 prevented hearing loss and the dendrites of the spiral g anglion neurons from swelling after noise-induced damage. The acute phase o f insult with the aminoglycoside antibiotic amikacin resulted in swollen af ferent dendrites beneath the inner hair cells. The chronic phase resulted i n complete hair cell loss and near-complete loss of spiral ganglion neurons . This damage caused a near-complete loss of hearing sensitivity as display ed by elevated (>90-dB sound pressure levels) auditory brainstem response t hresholds. The treatment of amikacin-exposed animals with MK801 gave only a partial protection of hearing. However, the combined treatment with NT3 an d MK801 in the amikacin-comprised ear resulted in improved mean hearing wit hin 20 dB of normal. Furthermore, hair cell loss was prevented in these ani mals and spiral ganglion neurons were completely protected. These results s uggest that the NMDA antagonist MK801 protects against noise-induced excito toxicity in the cochlea whereas the combined treatment of NT3 and MK801 has a potent effect on preserving both auditory physiology and morphology agai nst aminoglycoside toxicity.