In recent years, progress towards elucidating the molecular and cellular basis of neurodegeneration has accelerated due to our greater understanding of the role of proteases in degenerative conditions. In particular, the combined effect of increased intracellular Ca ++coupled to activation of calpains, intracellular proteases, in disorders such as stroke, ALS, Alzheimer's disease, Parkinson's disease, spinal cord injury and muscular dystrophy has suggested the existence of a common pathway initiated by different traumatic agents (e.g., isocheimal, mechanical trauma, or toxic injury) that activates the Ca++/calpain system resulting in cell death. For a number of years, CepTor Corp. has been advocating the use of calpain inhibitors, such as eupeptic, as therapeutic agents to attenuate certain degenerative conditions. Our studies have shown a potent, protective effect of calpain inhibitors in enervation atrophy and in a model of muscular dystrophy, the mdx mouse. Recently, we extended these studies to the auditory system. Our preliminary in vivo studies showed that infusion of eupeptic into the cochlea prevents the degeneration of sensory hair cells in the inner ear following acoustic over stimulation. Moreover, our in vivo studies show that eupeptic provides significant protection against aminoglycoside-induced hair cell damage in cochlear cultures. The purpose of the current project is to assess the efficacy of NeuroDur, a new and potentially more potent calpain eupeptic like compound. NeuroDur was formulated using a unique method by which the active portion of the eupeptic molecule is linked to cysteic acid, an analog of the taurine molecule that increases the concentration of NeuroDur into target tissues. The purpose of the current proposal is twofold. First, we will determine if systemic administration of NeuroDur protects against noise induced hearing loss by comparing the amount of hearing loss and hair cell loss in NeuroDur-treated animals versus control animals. NeuroDur will be administered at low, medium or high concentration to establish a dose-response curve. Second, we will determine if systemic administration of NeuroDur protects against kanamycin-induced hearing loss and hair cell loss. NeuroDur will be administered at one of three concentrations to establish a dose-response curve. If NeuroDur provides significant protection against noise or amino glycoside-induced hearing loss in animals, then limited phase-II trials will be initiated. Protection from noise-induced hearing loss and ototoxicity would address a major health problem. ? ?
