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.

声学爆炸暴露会导致听力损失和颅脑外伤（TBI），与记忆有关的变化功能障碍，认知下降，抑制神经发生和形成神经毒性Aβ：Zn斑块海马。据信，爆炸引起的内耳和海马变化是由氧化导致的应激，金属异性恋和神经毒性淀粉样蛋白β（Aβ）肽的表达增加。这提案将确定这些爆炸引起的记忆/认知定义是否可以使用我们的口服施用多功能氧化还原调节剂HK-2，以抑制氧化应激，金属异质症和 Aβ斑块形成。双作用HK-2：（a）隔离和重新分配自由过渡金属，以防止产生高毒性羟基自由基和（b）活性氧和氮自由基（ROS/RNS）的淬灭。 HK-2已显示可预防噪声引起的听力损失（NIHL），防止Aβ斑块形成在阿尔茨海默氏症的转基因小鼠中，并促进了神经毒性Aβ的降解：Zn斑块复合物相关患有痴呆症。大鼠将暴露于声音爆炸过压（ABO），并在没有耳朵保护的情况下进行为了创建TBI或TBI+NIHL的动物模型。 TBI和TBI+NIHL组将接受HK-2或安慰剂以确定HK-2是否有效防止（1）海马依赖性空间记忆定义，（2）海马Aβ的形成：Zn斑块和（3）海马神经发生的下降，（4）听力损失和毛细胞损失。成功证明了口服HK-2在预防记忆缺陷方面的效率，海马Aβ：Zn斑块和维持海马神经发生将代表主要的科学提前具有重大临床意义，可以提供必要的数据以提交SBIR第2阶段用于资助获得FDA研究新药所需的临床前和毒理学研究（IND）随后的临床研究应用。