Effect of Multifunctional Redox Modulator (MFRM) HK-2 on Acoustic Blast Overpressure and Cognitive Function

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Acoustic blasts exposure can induce hearing loss and traumatic brain injury (TBI), changes linked to memory dysfunction, cognitive decline, suppression neurogenesis and formation neurotoxic Aβ:Zn plaques in the hippocampus. The blast-induced changes in the inner ear and hippocampus are believed to result from oxidative stress, metal dyshomeostasis, and the increased expression of neurotoxic amyloid-β (Aβ) peptides. This proposal will determine if these blast-induced memory/cognitive deficits can be prevented using our orally- administered multifunctional redox modulator, HK-2, to suppress oxidative stress, metal dyshomeostasis, and Aβ plaque formation. Dual-acting HK-2: (a) sequesters and redistributes free transition metals preventing the generation of highly toxic hydroxyl radicals and (b) quenches reactive oxygen and nitrogen radicals (ROS/RNS). HK-2 has already been shown to protect against noise-induced hearing loss (NIHL), prevent Aβ plaque formation in Alzheimer's transgenic mice and facilitates the degradation of neurotoxic Aβ:Zn plaque complexes associated with dementia. Rats will be exposed to acoustic blast overpressures (ABO) with and without ear protection in order to create animal models of TBI or TBI+NIHL. The TBI and TBI+NIHL groups will be treated with HK-2 or placebo to determine if HK-2 is effective in preventing (1) hippocampal-dependent spatial memory deficits, (2) the formation of hippocampal Aβ:Zn plaques and (3) the decline in hippocampus neurogenesis, (4) hearing loss and hair cell loss. Successful demonstration of the efficacy of oral HK-2 in preventing memory deficits, hippocampal Aβ:Zn plaques and maintaining hippocampal neurogenesis would represent a major scientific advance with significant clinical implications that would provide the necessary data to submit an SBIR Phase 2 application to fund preclinical and toxicological studies required for obtaining an FDA investigational new drug (IND) application for subsequent clinical studies.