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

• 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
• 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

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.

暴露于声波可能导致听力损失和创伤性脑损伤 (TBI)，以及与记忆相关的变化 功能障碍、认​​知能力下降、抑制神经发生和形成神经毒性 Aβ:Zn 斑块 海马体。爆炸引起的内耳和海马体变化被认为是氧化作用的结果 应激、金属稳态失衡以及神经毒性淀粉样蛋白-β (Aβ) 肽表达增加。这 该提案将确定是否可以使用我们的口腔预防这些爆炸引起的记忆/认知缺陷 给予多功能氧化还原调节剂 HK-2，以抑制氧化应激、金属稳态失衡和 Aβ斑块形成。双作用 HK-2：(a) 隔离并重新分配游离过渡金属，防止 产生剧毒的羟基自由基，并且 (b) 淬灭活性氧和氮自由基 (ROS/RNS)。 HK-2 已被证明可以预防噪音性听力损失 (NIHL)，防止 Aβ 斑块形成 在阿尔茨海默病转基因小鼠中，促进神经毒性 Aβ:Zn 斑块复合物的降解 患有痴呆症。大鼠将在有或没有耳朵保护的情况下暴露于声波超压 (ABO) 以创建 TBI 或 TBI+NIHL 动物模型。 TBI 和 TBI+NIHL 组将接受 HK-2 或 安慰剂以确定 HK-2 是否能有效预防 (1) 海马依赖性空间记忆缺陷，(2) 海马 Aβ:Zn 斑块的形成以及 (3) 海马神经发生的下降，(4) 听力损失 和毛细胞损失。成功证明口服 HK-2 在预防记忆缺陷方面的功效， 海马 Aβ:Zn 斑块和维持海马神经发生将代表一项重大科学 具有重大临床意义的进展将为提交 SBIR 第 2 阶段提供必要的数据 申请资助获得 FDA 研究性新药所需的临床前和毒理学研究 （IND）申请后续临床研究。