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…

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 ASS: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-SS (ASS) 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 ASS 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 ASS plaque formation in alzheimer's transgenic mice and facilitates the degradation of neurotoxic ASS: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 ASS: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 ASS: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.