Multifunctional Antioxidant to Prevent Noise-Induced Hearing Loss

Noise induced hearing lossNIHLis the most common occupational disease for which no clinically effective drug is availableSince NIHL involves oxidation linked loss of sensory hair cells and auditory neurons in the cochleathere is a need for potent and effective antioxidants that offer protection to these tissuesIn preliminary studies we have observed that the orally administered multifunctional antioxidant HKthat uses the innovative therapeutic strategy of combining both metal attenuating properties with free radical scavenging activities into one moleculeprovides promising preventive protection against NIHL in ratsThis proposal seeks to confirmclarifyand expand on this observation by conducting in vivo dose response studies in rats to determine the optimal dose of HKrequired for NIHL protectionSubsequentlyintervention studies will be conducted to determine whether the optimal dose of HKis only protective when administered prior to damaging noise exposure or whether protection can also be obtained through intervention when administered at the onset of damaging noise exposure or even hours after exposureTo clarify the mechanism of action of HKin vitro studies will be conducted in which are exposed to reactive oxygen speciesROSwhich include superoxidehydrogen peroxide and hydroxyl radicalsas well as reactive nitrogen speciesRNSderived from nitric oxideHKits monofunctional analogsand parent compound will be used to define the relative importance of metal chelation versus free radical scavenging activitythe importance of mitochondrial function protection in these cochlear cells in the treatment of NIHLand to demonstrate that HKcan protect against different sources of oxidative stressThe data obtained will provide the basis for an SBIR Phaseapplication to fund the necessary preclinical and toxicological studies required for obtaining a FDA investigational new drugINDapplication to develop multifunctional antioxidants for the clinical treatment of NIHLHouse Ear Institute Organ of CortiHEI OCcellsPrevention and Intervention studies will be conducted in rats to demonstrate that orally administered multifunctional antioxidants that independently scavenge free radicals while also binding select transition metals that participate in hydroxyl radical formation can protect against noise induced hearing lossNIHLIn additioncultured House Ear Institute Organ of CortiHEI OCcells exposed to various reactive oxygen speciesROSand reactive nitrogen speciesRNSwill be used to determine the specific mechanisms of action of multifunctional antioxidants in their protection against NIHL