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

声爆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：锌斑块 海马体。冲击波引起的内耳和海马体的变化被认为是氧化的结果 应激、金属代谢紊乱和神经毒性淀粉样蛋白-β(A-β)多肽表达增加。这 一项提案将确定这些爆炸诱发的记忆/认知障碍是否可以通过我们的口服- 给予多功能氧化还原调节剂HK-2，以抑制氧化应激，金属代谢失调，以及 一种β斑块形成。双效HK-2：(A)封存和重新分配自由过渡金属，防止 产生剧毒的羟基自由基，并(B)熄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，防止Aβ斑块形成 在阿尔茨海默病转基因小鼠中，并促进神经毒性Aβ：锌斑块复合体的降解 患有痴呆症。大鼠将暴露在有或没有耳朵保护的声爆超压(ABO)中 建立创伤性脑损伤或脑外伤+NIHL动物模型。脑损伤组和脑损伤+NIHL组应用HK-2或 安慰剂以确定HK-2是否有效预防(1)海马区依赖的空间记忆缺陷，(2) 海马区Aβ：锌斑块的形成和(3)海马神经发生的下降，(4)听力损失 和毛细胞丢失。成功证明口服HK-2预防记忆障碍的功效， 海马区Aβ：锌斑块与维持海马区神经发生将代表重大科学意义 具有重大临床意义的进展，将提供提交SBIR第二阶段所需的数据 申请资助为取得FDA试验性新药所需的临床前研究及毒理学研究 (IND)申请进行后续临床研究。

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.