Acoustic blasts exposure can induce hearing loss and traumatic brain injury (TBI), changes linked to memorydysfunction, cognitive decline, suppression neurogenesis and formation neurotoxic Aβ:Zn plaques in thehippocampus. The blast-induced changes in the inner ear and hippocampus are believed to result from oxidativestress, metal dyshomeostasis, and the increased expression of neurotoxic amyloid-β (Aβ) peptides. Thisproposal 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, andAβ plaque formation. Dual-acting HK-2: (a) sequesters and redistributes free transition metals preventing thegeneration 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 formationin Alzheimer's transgenic mice and facilitates the degradation of neurotoxic Aβ:Zn plaque complexes associatedwith dementia. Rats will be exposed to acoustic blast overpressures (ABO) with and without ear protection inorder to create animal models of TBI or TBI+NIHL. The TBI and TBI+NIHL groups will be treated with HK-2 orplacebo 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 lossand 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 scientificadvance with significant clinical implications that would provide the necessary data to submit an SBIR Phase 2application to fund preclinical and toxicological studies required for obtaining an FDA investigational new drug(IND) application for subsequent clinical studies.
Public Health Relevance Statement: Hearing loss is linked to cognitive decline and is an independent risk factor for dementia. By
subjecting rats with or without ear plugs to acoustic blast overpressure, and treatment with HK-
2, these proposed studies are designed to expand on our original observation that
multifunctional redox modulators such as HK-2 reduce noise-induced hearing loss by
demonstrating that these compounds also reduce hippocampal spatial memory loss, and
possibly the effects of traumatic brain injury on the hippocampus.
Project Terms: 