Metabolic origin of oxidative stress injury in brain ischemia/reperfusion

脑缺血/再灌注氧化应激损伤的代谢起源

• 批准号: 10354477
• 负责人: Alexander Galkin
• 金额: $ 25.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354477
• 关键词: Adenosine; Affect; Amino Acids; Ammonia; Ammonium; Bioenergetics; Blood flow; Brain; Brain Death; Brain Hypoxia; Brain Hypoxia-Ischemia; Brain Injuries; Brain Ischemia; Cell Death; Cerebral Palsy; Cerebrum; Citric Acid Cycle; Clinical Research; Complex; DNA Damage; Data; Deamination; Enzymes; Event; Failure; Flavins; Generations; Glucose; Glutamates; Glutamine; Glycolysis; Goals; Guanine; Hippocampus (Brain); Hypoxia; Hypoxic-Ischemic Brain Injury; Impairment; Individual; Infant; Infant Mortality; Injury; Intervention; Ischemia; Ischemic Stroke; Lead; Lesion; Life; Lipid Peroxidation; Metabolic; Metabolic Pathway; Mitochondria; Modeling; Molecular Target; Morbidity - disease rate; Mus; Necrosis; Neonatal; Neurologic; Neurons; Outcome; Oxidative Stress; Oxygen; Pathology; Pathway interactions; Patients; Perinatal Hypoxia; Perinatal mortality demographics; Pharmacology; Production; Publishing; Purine Nucleotides; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Rice; Role; Signal Pathway; Slice; Source; Stroke; Testing; Therapeutic; Therapeutic Intervention; Tissues; Wild Type Mouse; Work; amino acid metabolism; base; brain cell; brain tissue; deamidation; deprivation; dihydrolipoamide dehydrogenase; disability; hypoxia neonatorum; hypoxic ischemic injury; improved; improved outcome; inhibitor; ketoglutarate dehydrogenase; life time cost; metabolomics; mitochondrial permeability transition pore; negative affect; neonatal brain; neonatal mice; neonate; nitrogen metabolism; novel; oxidative damage; pre-clinical; stroke model; targeted treatment; tissue injury

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.

概括： 全球每年因围产期缺氧缺血 (HI) 损伤而死亡的人数约为 120 万人。 在美国，围产期脑损伤仍然是脑瘫和生命危险的主要原因之一。 长期神经功能障碍。脑瘫患者一生的费用估计为 每个受影响的个人损失 115 亿美元。这表明需要基于以下方面的治疗策略： 更好地了解 HI 损伤的机制。 HI-再灌注相关的糖酵解、克雷布斯循环、线粒体能量破坏 生产、氮代谢和氧化应激对大脑的存活产生负面影响 脑细胞。这些是导致 HI 脑组织损伤的主要因素。然而， 既不知道所谓的二次能源衰竭的确切机制，也不知道其起源 缺血/再灌注中的氧化应激是已知的。我们建议大脑缺氧 导致氨基酸和嘌呤核苷酸的降解，导致积累 氨（NH4+）。这反过来又激活了活性氧 (ROS) 的产生 再灌注过程中线粒体酶α-酮戊二酸脱氢酶引起氧化 受伤。我们的初步数据确定了 HI 大脑中存在这种代谢级联 促使进一步研究。 在拟议的研究中，我们将追求增加 ROS 生成的新假设 线粒体生物能学衰竭与缺血性 NH4+ 积累相关。这是 与 HI 和中风模型中观察到的所有实验数据一致。这是一个新的，就目前而言 未被认识和探索的损伤机制，这解释了已发表的实验 数据显示脑缺血/再灌注期间 ROS 短暂爆发。获得的数据在 这项研究将显着改变目前神经元起源的范式 缺血/再灌注损伤。我们的目标是确定 NH4+ 在刺激 新生儿 HI 生物能学失败期间线粒体 ROS 的产生。临床前影响 该项目的目的是为进一步的临床研究提供理论依据，旨在减少术后 你好，脑损伤。