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: 8583717
• 负责人: ROBERT T MALLET
• 金额: $ 4.33万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583717
• 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）：在美国，心脏骤停是导致死亡的主要原因，对大脑和其他内脏器官造成严重缺血。即使恢复了心律，大多数心脏骤停患者最终还是会死于不可逆的脑损伤的破坏性影响，许多幸存者会遭受持续的、使人衰弱的神经功能障碍。尽管进行了广泛的临床前和临床研究，但预防心脏骤停患者脑损伤的实用治疗仍然难以捉摸。最近，促红细胞生成素激素被证明通过激活细胞保护信号级联抑制神经元凋亡和抑制破坏性炎症来保护脑免受缺血性损伤。然而，由于促红细胞生成素不能容易地穿过血脑屏障，因此需要大剂量来实现显著的神经保护，并且最近在心脏骤停患者中静脉内促红细胞生成素的临床试验的结果令人失望。神经元和星形胶质细胞可以表达和合成促红细胞生成素，并且在脑内诱导促红细胞生成素表达可以赋予强大的神经保护，同时绕过血脑屏障。最近，我们证明了丙酮酸，一种天然的中间代谢物和抗氧化剂，诱导新的促红细胞生成素的表达和信号在心肌停滞，重要的是，这些反应仍然强劲4小时后丙酮酸清除。此外，在心肺复苏（CPR）过程中静脉输注丙酮酸可预防心脏骤停后3天的神经功能损害和神经元凋亡。血脑屏障内的高亲和力、高容量转运机制有效地将丙酮酸递送至脑实质。这项研究将测试丙酮酸通过诱导脑内促红细胞生成素表达和信号传导来预防脑损伤和保护心脏骤停后神经认知功能的假设。这一假设将在经历室颤心脏骤停、CPR、辅助性反电击和恢复的犬中得到解决。将在CPR期间和前55分钟恢复期间静脉输注丙酮酸盐或对照NaCl，或在恢复心律和脑灌注后120-180分钟以延迟方式静脉输注。在心脏骤停-复苏后5 h、2 d和4 d活检的易损脑区中测量促红细胞生成素mRNA和蛋白含量、信号激酶活化、中性粒细胞浸润以及促凋亡半胱天冬酶、促炎性基质金属蛋白酶和细胞保护酶内皮型一氧化氮合酶的活性。丙酮酸的神经保护机制及其在脑内诱导促红细胞生成素信号传导的能力的关键信息将为这种神经保护现象的最终临床开发提供必要的基础。