New approaches for inner ear therapy with glutamate antagonists

In the mammalian cochlea neurotransmission between inner hair cells and eff erent auditory neurons is probably mediated by glutamate or another related excitatory amino acid. Neurotoxicity induced by excessive glutamate releas e seems to play a crucial role in some pathological conditions of the cochl ea. such as ischaemia or noise trauma. Thus, glutamate antagonists may be a new therapeutic strategy for different inner ear diseases. Because of thei r potential severe side-effects only a few glutamate antagonists have so fa r been adopted for clinical use. Wt used microiontophoretic techniques to c ompare the effects of memantine and caroverine on the glutamatergic transmi ssion of inner hair cells of the guinea pig and tested the possibility of a local administration of memantine to the cochlea with a micropump. Memanti ne selectively inhibited the NMDA (N-methyl-D-aspartate) stimulated activit y while caroverine blocked NMDA as well as AMPA (alpha-amino-3-hydroxy-5-me thylisoxazole-4-propionic acid) induced activity of inner hair cell afferen ts, With a Row rate of 1 mu l/h the local administration of memantine via a cochleotomy was succeeded in a reversible blockade of the spontaneous and the NMDA induced firing of inner hair cell afferents. These results suggest that local application to the cochlea could be a feasible way to administe r glutamate antagonists in sufficient amounts while avoiding systemic side- effects.