Drugs to Stimulate Neurite Regeneration from Damaged Cochlear Neurons

Continuous exposure to high noise levels such as that produced by ship and jet engines and by blast exposure or weapon firing can cause Noise Induced Hearing Loss (NIHL). The majority of NIHL cases reported are of the sensorineural type. This occurs when the acoustic stimulation or shock wave is so powerful or of such consistent duration that it directly damages the auditory nerve and/or destroys the hair cells, the sound-sensing cells of the inner ear. When hair cells are destroyed, they cannot naturally grow back and the cochlear spiral ganglion neurons that originally connected the hair cells with the brain die or degenerate. Hearing loss from acoustic injury can be as profound as total deafness or as seemingly mild as a slow, inexorable degeneration of neurons over time. Moreover, not only can hearing be damaged during insult that causes Traumatic Brain Injury (TBI), but it is also negatively affected by medical interventions to treat TBI, including the administration of ototoxic but life-saving antibiotics. As hearing loss significantly impairs the communication necessary for job performance in the Armed Forces and quality of life after service, this disability is a significant problem for the Navy, the Marines, the Army and others in the Military. Adding to the decay in job performance caused by auditory dysfunction and the premature retirement of otherwise highly skilled and seasoned personnel, the financial burden to the Veterans Administration to care for affected veterans has risen to an annual cost of over $1 billion. This project is meant to build on the foundation we laid down during prior ONR funding. Under that ONR support, we developed a novel method for discovery of drugs aimed at inducing regrowth of nerve fibers from spiral ganglion neurons in vitro and used it to screen over 1000 compounds. We promoted the most promising chemical candidate to evaluation in a guinea pig model of noise induced hearing loss, using physiologic and confocal imaging analyses and pioneered the use of X-ray tomography to visualize and count spiral ganglion neurons in intact (unsectioned) cochleas of noise and drug exposed cochleas. We showed that the compound we identified in our screen protects against noise induced hearing loss. Here we propose to build on the discoveries we made in the initial project by continuing to evaluate the effects of a promising drug candidate on noise induced hearing loss, to continue to evaluate new chemical compound libraries for their abilities to promote spiral ganglion neurite elongation, to explore more efficient ways to test drugs in vivo, and to continue to evaluate promising new compounds in animal models of noise induced hearing loss