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

多功能氧化还原调节剂 (MFRM) HK-2 对声波超压和认知功能的影响

基本信息

批准号：
10546778
负责人：
PETER F KADOR
金额：
$ 14.99万
依托单位：
THERAPEUTIC VISION, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546778
关键词：
AD transgenic mice Acoustics Aging Amyloid beta-Protein Animal Model Animals Auditory Biological Markers Brain Cataract Clinical Clinical Research Cochlea Cochlear Hearing Loss Cognitive Cognitive deficits Collaborations Complex Control Groups Data Dementia Dose Ear Earplug Exposure to Eye Funding Generations Hair Cells Hearing Hearing Tests Hippocampal Formation Hippocampus (Brain)Histologic Histopathology Human Hydroxyl Radical Impaired cognition Impairment In Vitro Investigational New Drug Application Iron Labyrinth Learning Link Maps Memory Memory Loss Memory impairment Metals Military Personnel Mitochondria Neurons Nitrogen Noise-Induced Hearing Loss Oral Outcome Oxidation-Reduction Oxidative Stress Oxygen Peptide Hydrolases Phase Pilot Projects Placebos Pyrrolidines Rattus Reaction Resistance Retinal Degeneration Risk Factors Scientific Advances and Accomplishments Senile Plaques Small Business Innovation Research Grant Social Interaction Structure Superoxides Testing Toxicology Transition Elements Traumatic Brain Injury Waxes age related amyloid formation base blast exposure clinically relevant cognitive function cognitive performance dementia risk design epidemiology study experimental study hearing impairment memory acquisition memory retention neurogenesis neurotoxic noise exposure novel novel therapeutic intervention pre-clinical preservation prevent prevent hearing loss relating to nervous system spatial memory

项目摘要

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.

声波爆炸暴露会导致听力丧失和创伤性脑损伤（TBI），这是与记忆有关的变化