Screening For and Preclinical Evaluation of Drugs for Hearing Loss

In the armed forces, military personnel are continually exposed to acoustic insults that can result in severe inner ear damage and promote hearing impairment and deafness. As hearing loss significantly impairs the communication necessary for job performance in the Armed Forces and quality of life and job performance after service, this disability is a significant problem for the Military as well as for the Veterans Administration, whose responsibility it is to care for service related injuries. At present, there are no FDA approved drugs to treat hearing loss. This study builds on the discoveries made in two past ONR grants. In those grants, to address the degeneration of nerve fibers after noise insult, an original and unique approach was developed to screen chemical compounds for their ability to promote neurite growth from mammalian spiral ganglion neurons in culture. The assay found positive activity in certain “statins” (HMG-CoA Reductase inhibitors) that were elevated to evaluation in a guinea pig model of noise induced hearing loss. That study unexpectedly found that a statin directly delivered to the cochlea protected against high level noise and that retention of cochlear hair cells was associated with this protection. The present proposal continues to screen chemical compound libraries for other neurite promoting activity, follows up on previous observations and moves forward in evaluating possible biochemical mechanisms underlying the neurite elongating and hearing protective effects of statins in vitro. To do this, cell culture of dissociated spiral ganglia from newborn mice will be used for assaying of chemical libraries and for determining possible mechanisms of statin induced neurite elongation. In vivo studies in mice or guinea pigs will address the function of delayed statin administration on cochlear spiral ganglion neurites after high level noise exposure, evaluate possible biochemical mechanisms underlying the statin effects on hearing, follo