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

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.