The primary objective of these studies is to test and develop pharmacologic agents to protect against noise-induced hearing loss (NIHL). The long-term objective is to develop agents for oral administration in clinical populations. The primary hypothesis is that pharmacologically optimizing the glutathione pathway will ameliorate or prevent NIHL and that this protection can be obtained by either injection or by oral administration of carefully selected glutathione enhancing agents. The secondary hypothesis is that noise exposure will alter the glutathione pathway as measured by the ratio of reduced to oxidized glutathione and the affiliated enzymes glutathione reductase (GR) and glutathione peroxidase (GSH-Px) during the first 6 hours of noise exposure and that these changes will correlate with the level of lipid peroxidation as measured by malondialdehyde (MDA) levels. The first specific aim is to determine the time course of any changes in the cochlear levels of reduced glutathione, and the ratio of reduced (GSH) vs. oxidized (GSSG) glutathione prior to noise exposure, and .5, 2, 4, and 6 hours after onset of noise exposure.
This aim will be accomplished by measuring cochlear glutathione, both the reduced GSH and oxidized GSSG, in animals sacrificed at those times. The critical measures will be the reduced GSH, and the GSH/GSSG ratio, a measure of oxidative stress. The second specific aim is to determine the time course of any changes in cochlear GR and GSH-Px, critical enzymes of the glutathione anti-oxidant pathway, at those same times. The third specific aim is to determine the time course of changes in cochlear lipid peroxidation at those same times. The second and third aims will be accomplished by measuring GR, GSH-Px, and MDA, a marker for cell membrane oxidative damage, in animals sacrificed at those times. The fourth specific aim is to determine the efficacy of 3 putative otoprotective agents in reducing noise induced cochlear damage with auditory brainstem response thresholds and outer hair cell counts as primary measures. Protection efficacy will also be measured by GSH/GSSG, GR, GSH-Px, and MDA measures. The fifth specific aim is to compare the efficacy of these same agents orally administered to the IP administration, utilizing the same outcome measures. These studies should lay the basis for clinical trials of oral agents to prevent NIHL.
