Metabolic Origin of Oxidative Stress Injury in Brain Ischemia/Reperfusion

摘要： 全球每年约有120万人死于围产期缺氧缺血(HI)。 在美国，围产期缺氧脑损伤仍然是导致脑瘫和生命的主要原因之一。 长期的神经功能障碍。据估计，脑瘫患者的终生成本为 每个受影响的人115亿美元。这就决定了治疗策略的必要性。 更好地了解HI损伤的机制。 缺氧再灌注相关糖酵解、Krebs循环、线粒体能量的中断 生产、氮代谢和氧化应激对脑组织的存活有负面影响 脑细胞。这些都是导致HI时脑组织损伤的主要因素。然而， 无论是所谓的二次能源故障的确切机制，还是 氧化应激在缺血/再灌流中的作用是已知的。我们认为大脑缺氧 导致氨基酸和嘌呤核苷酸的降解，从而导致 氨(NH4+)。这反过来又激活了活性氧物种(ROS)的产生 线粒体酶-酮戊二酸脱氢酶在再灌流中引起氧化 受伤。我们的初步数据证实了HI脑中存在这种代谢级联反应 促进了进一步的研究。 在拟议的研究中，我们将继续研究增加ROS生成的新假设 线粒体生物能量学失效与缺血型NH4+蓄积有关。这是 与在HI和卒中模型中观察到的所有实验数据一致。这是一种新的，就目前而言 未被认识和未被探索的损伤机制，这解释了发表的实验 显示脑缺血/再灌流过程中ROS瞬间爆发的数据。年获得的数据 这项研究将极大地改变目前神经元起源的范式 缺血/再灌流损伤。我们的目标是确定NH4+在刺激细胞生长中的主要作用。 新生儿缺氧缺血性脑病生物能失效时线粒体ROS的产生。临床前的影响 这一项目的目的是为进一步的临床研究提供理论基础，旨在减少 嗨，脑部受伤。

Summary: The annual worldwide mortality from perinatal hypoxic-ischemic (HI) insult is ~1.2 million. In the US, perinatal HI-brain injury remains one of the major causes of cerebral palsy and life- long neurological disability. The lifetime cost for patients with cerebral palsy is estimated to be $11.5 billion per affected individual. This dictates a need for therapeutic strategies based on a better understanding of the mechanisms of HI injury. HI-reperfusion-associated disruption in glycolysis, the Krebs cycle, mitochondrial energy production, nitrogen metabolism, and oxidative stress negatively affect the survival of cerebral brain cells. These are the major factors contributing to brain tissue damage in HI. However, neither the exact mechanisms of the so-called secondary energy failure nor the origin of oxidative stress in ischemia/reperfusion are known. We propose that brain oxygen deprivation leads to degradation of amino acids and purine nucleotides resulting in the accumulation of ammonia (NH4+). This, in turn, activates reactive oxygen species (ROS) production by the mitochondrial enzyme -ketoglutarate dehydrogenase during reperfusion causing oxidative injury. Our preliminary data identify the presence of this metabolic cascade in the HI brain prompting further study. In the proposed study, we will pursue the novel hypothesis that increased ROS generation and mitochondrial bioenergetics failure correlated with ischemic NH4+ accumulation. This is consistent with all experimental data observed in HI and stroke models. This is a new, insofar unrecognized, and unexplored mechanism of injury, which explains the published experimental data showing the transient burst of ROS during brain ischemia/reperfusion. The data obtained in this study will significantly alter the current paradigm of the origin of neuronal ischemia/reperfusion damage. We aim to define the major role of NH4+ in stimulation of mitochondria ROS production during bioenergetics failure in neonatal HI. The preclinical impact of this project is to provide a rationale for further clinical studies aimed at the reduction of post- HI brain injury.