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

声冲击波暴露可导致听力损失和创伤性脑损伤（TBI），这些变化与记忆有关 功能障碍、认知功能减退、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的变化被认为是由氧化应激引起的。 应激、金属稳态失调和神经毒性淀粉样蛋白-β（Aβ）肽表达增加。这 这项提案将确定这些爆炸引起的记忆/认知缺陷是否可以通过我们的口服- 施用多功能氧化还原调节剂HK-2以抑制氧化应激、金属稳态失调，以及 Aβ斑块形成。双作用HK-2：（a）螯合和重新分配游离过渡金属，防止 产生高毒性的羟基自由基和（B）淬灭活性氧和氮自由基（ROS/RNS）。 HK-2已被证明可以预防噪声性听力损失（NIHL），防止Aβ斑块形成， 在阿尔茨海默氏症转基因小鼠中，促进神经毒性Aβ：锌斑复合物的降解， 患有痴呆症大鼠将暴露于声冲击波超压（ABO），有和没有耳朵保护， 建立TBI或TBI+NIHL动物模型。TBI和TBI+NIHL组将用HK-2或TBI +NIHL治疗。 安慰剂，以确定HK-2是否有效预防（1）大脑皮层依赖性空间记忆缺陷，（2） 海马Aβ：Zn斑块的形成;（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预防记忆缺陷的功效， 海马Aβ：锌斑和维持海马神经发生将代表一个主要的科学 具有重大临床意义的进展，将为提交SBIR II期提供必要的数据 申请资助获得FDA研究新药所需的临床前和毒理学研究 (IND)用于后续临床研究。

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.