Receptor Pharmacological Models for Inner Ear Therapies with Emphasis on Glutamate Receptors: A Survey

With the aid of microiontophoretic techniques we evaluated the action of different postsynaptic glutamate receptor subtypes that mediate neurotransmission between the inner hair cell and the afferent neuron. The sensory input is modulated by axodendritic efferents. In the central nervous system, excessive activation of glutamate receptors is thought to be responsible for a wide variety of neurotoxic actions, and calcium is involved in the etiology of glutamate-induced cell damage. Glutamatergic neurotoxicity may form an appropriate pathophysiological model to explain a variety of inner ear diseases characterized by acute or progressive hearing loss and tinnitus. In clinical trials, three sites of action are thought to attenuate glutamatergic otoneurotoxicity: presynaptically, via the reduction of excessive transmitter release; postsynaptically, via competitive or noncompetitive receptor antagonism; and intracellularly. via blockage of glutamate receptor-dependent calcium stores. The drugs discussed in this paper are currently available clinically and have only recently been found to attenuate glutamate toxicity. Magnesium and the quinoxaline derivative Caroverine, which have already been tested in humans, exhibit a statistically significant otoneuroprotective action in noise-induced hearing loss and tinnitus. The intensive search for further drugs that enhance the survival of cochlear afferents without disrupting acoustic signal processing is one of the main goals of research in clinical otoneuropharmacology in the near future.