Pyruvate: Powerful Brain Protection after Cardiac Arrest

丙酮酸：心脏骤停后强大的大脑保护

• 批准号: 8329601
• 负责人: ROBERT T MALLET
• 金额: $ 31.72万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329601
• 关键词: Accident and Emergency department; Address; Affinity; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Astrocytes; Biopsy; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain Ischemia; Brain region; Canis familiaris; Cardiopulmonary Bypass; Cardiopulmonary Resuscitation; Caspase; Cause of Death; Cerebrum; Cessation of life; Clinical; Clinical Research; Clinical Trials; Dose; Electric Countershock; Enzymes; Erythropoietin; Event; Fostering; Foundations; Goals; Heart Arrest; Hippocampus (Brain); Hormones; Hospitals; Hour; Impairment; Induced Heart Arrest; Inflammation; Inflammatory; Infusion procedures; Injury; Intervention; Intravenous; Investigation; Ischemia; Ischemic Brain Injury; Knowledge; Matrix Metalloproteinases; Measures; Messenger RNA; Mission; Modality; Myocardium; Neurocognitive; Neurologic; Neurons; Neutrophil Infiltration; Organ; Outcome; Perfusion; Permanent Vegetative States; Phosphotransferases; Production; Proteins; Public Health; Pyruvate; Quality of life; Recovery; Research; Resistance; Resuscitation; Risk; Signal Transduction; Staging; Survivors; System; Testing; United States; Ventricular Fibrillation; Work; base; clinical practice; disability; dosage; effective therapy; experience; heart rhythm; human NOS3 protein; improved; intravenous administration; minimally invasive; nervous system disorder; neuron apoptosis; neuroprotection; novel; pre-clinical research; preclinical study; prevent; response; restoration; stem

DESCRIPTION (provided by applicant): The leading cause of death in the United States, cardiac arrest imposes profound ischemia on the brain and other internal organs. Even when cardiac rhythm is restored, most cardiac arrest victims eventually succumb to the devastating effects of irreversible brain damage, and many survivors suffer persistent, debilitating neurological impairment. Despite extensive preclinical and clinical research, a practical treatment to prevent brain damage in cardiac arrest victims remains elusive. Recently the hormone erythropoietin was shown to protect brain from ischemic injury by activating cytoprotective signaling cascades which suppress neuronal apoptosis and dampen destructive inflammation. However, because erythropoietin cannot readily traverse the blood-brain barrier, massive dosages are required to achieve significant neuroprotection, and outcomes of recent clinical trials of intravenous erythropoietin in cardiac arrest victims have been disappointing. Neurons and astrocytes can express and synthesize erythropoietin, and induction of erythropoietin expression within the brain could confer powerful neuroprotection while circumventing the blood brain barrier. Recently, we demonstrated that pyruvate, a natural intermediary metabolite and antioxidant, induced novel erythropoietin expression and signaling in arrested myocardium; importantly, these responses remained robust 4 hours after pyruvate had cleared. Moreover, intravenous pyruvate infusion during cardiopulmonary resuscitation (CPR) prevented subsequent neurological impairment and neuronal apoptosis 3 days after cardiac arrest. A high-affinity, high-capacity transport mechanism within the blood brain barrier efficiently delivers pyruvate to the brain parenchyma. This investigation will test the hypothesis that pyruvate prevents brain injury and preserves neurocognitive function after cardiac arrest by inducing erythropoietin expression and signaling within the brain. This hypothesis will be addressed in dogs subjected to ventricular fibrillation cardiac arrest, CPR, defibrillatory countershocks and recovery. Pyruvate or control NaCl will be infused intravenously during CPR and the first 55 min recovery, or in a delayed manner 120-180 min after restoration of cardiac rhythm and brain perfusion. Erythropoietin mRNA and protein content, signaling kinase activation, neutrophil infiltration, and activities of proapoptotic caspases, pro-inflammatory matrix metalloproteinases, and the cytoprotective enzyme endothelial nitric oxide synthase will be measured in vulnerable brain regions biopsied at 5 h, 2 d and 4 d after cardiac arrest-resuscitation. Crucial information on pyruvate's neuroprotective mechanisms and its ability to induce erythropoietin signaling within the brain will provide the essential foundation for eventual clinical exploitation of this cerebroprotective phenomenon.

描述（由申请人提供）：美国的主要死亡原因，心脏骤停对大脑和其他内部器官施加了深刻的缺血。即使恢复了心律，大多数心脏骤停的受害者最终屈服于不可逆转的脑损伤的毁灭性影响，许多幸存者遭受了持久的神经系统损害。尽管进行了广泛的临床前和临床研究，但一种用于防止心脏骤停受害者脑损伤的实际治疗方法仍然难以捉摸。最近，通过激活抑制神经元细胞凋亡和抑制破坏性炎症的细胞保护信号级联反应，表现出激素促红细胞生成素可保护大脑免受缺血性损伤。但是，由于促红细胞生成素无法轻易穿越血脑屏障，因此需要大量剂量才能获得明显的神经保护作用，并且最近在心脏骤停受害者中静脉内红细胞生成素的临床试验结果令人失望。神经元和星形胶质细胞可以表达和合成促红细胞生成素，并且在大脑中诱导红细胞生成素的表达可以赋予强大的神经保护作用，同时绕过血脑屏障。最近，我们证明了一种天然的中间代谢产物和抗氧化剂丙酮酸诱导的新型促红细胞生成素表达和信号传导。重要的是，这些反应在丙酮酸清除后4小时保持稳健。此外，心肺复苏期间（CPR）期间静脉内丙酮酸输注可阻止心脏骤停后3天后神经系统损伤和神经元凋亡。血脑屏障内的高亲和力，高容量的运输机制有效地将丙酮酸输送到脑实质。这项研究将检验以下假设，即丙酮酸可以通过诱导脑抑制脑损伤并保留心脏骤停后神经认知功能，通过诱导红细胞生成素的表达和脑中的信号传导来保留神经认知功能。该假设将在经受心室纤颤，心脏骤停，CPR，除颤性反震和恢复的狗中解决。丙酮酸或对照NaCL将在心肺复苏术和最初的55分钟恢复期间静脉注入，或以延迟的方式恢复心律和脑灌注后120-180分钟。红细胞生成素mRNA和蛋白质含量，信号激酶激活，嗜中性粒细胞浸润以及促凋亡胱天蛋白酶的活性，促炎性基质金属蛋白酶酶以及细胞保护酶内皮氧化氮氧化物合成酶的细胞保护酶均可在5层中施加到5层中，可在5层中进行5层捕获，并在5层中进行5层和4 d d d d d d d d d d d d d d d d d d d.有关丙酮酸神经保护机制及其在大脑内诱导红霉素信号传导的能力的关键信息将为最终临床剥削这种脑保护现象提供必不可少的基础。