Activation of Pyruvate Dehydrogenase Activity by Dichloroacetate Improves Survival and Neurologic Outcomes After Cardiac Arrest in Rats.
Activation of Pyruvate Dehydrogenase Activity by Dichloroacetate Improves Survival and Neurologic Outcomes After Cardiac Arrest in Rats.
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二氯乙酸激活丙酮酸脱氢酶活性可改善大鼠心脏骤停后的存活率和神经系统结果。
DOI：
10.1097/shk.0000000000000971
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发表时间：
2018
期刊：
影响因子：
3.1
通讯作者：
Tang Wanchun
中科院分区：
文献类型：
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作者：
Wang Peng;Chen Mingdi;Yang Zhengfei;Yu Tao;Zhu Jie;Zhou Lili;Lin Jiali;Fang Xiangshao;Huang Zitong;Jiang Longyuan;Tang Wanchun
目前没有药物干预可用于为心脏骤停患者提供神经保护。二氯乙酸（DCA）是丙酮酸脱氢酶激酶抑制剂，其激活丙酮酸脱氢酶（PDH），并通过促进丙酮酸流入克雷布斯循环来增加细胞三磷酸腺苷（ATP）的产生。在本研究中，我们研究了DCA对窒息心脏骤停大鼠模型复苏后神经损伤的影响。通过气管插管夹闭建立窒息性心脏骤停。将111只大鼠随机分为3组：假手术组（Sham）、对照组（Control）和DCA干预组（DCA干预组）。DCA干预组于自主循环恢复（ROSC）后15 min腹腔注射负荷剂量为80 mg/kg的DCA，对照组注射等量生理盐水。DCA治疗增加了3天的生存时间，并降低了ROSC后24，48和72小时的神经功能缺损评分。苏木精-伊红染色和TdT介导的dUTP缺口末端标记法检测海马角氨区细胞凋亡和神经元损伤。此外，DCA还能降低ROSC后海马和皮层肿瘤坏死因子α和白细胞介素1β mRNA的表达。此外，DCA治疗显着增加ATP的生产，PDH活性，并降低血糖，乳酸，脑丙酮酸水平后ROSC。我们的研究结果表明，DCA对心脏骤停后脑损伤具有神经保护作用，其有益作用与通过激活PDH活性增加脑线粒体能量代谢有关。
No pharmacological interventions are currently available to provide neuroprotection for patients suffering from cardiac arrest. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase inhibitor, which activates pyruvate dehydrogenase (PDH), and increases cell adenosine triphosphate (ATP) production by promoting influx of pyruvate into the Krebs cycle. In this study, we investigated the effects of DCA on post-resuscitation neurological injury in an asphyxial cardiac arrest rat model. Asphyxial cardiac arrest was established by endotracheal tube clamping. A total of 111 rats were randomized into three groups: Sham group, Control group, and DCA intervention group. Animals in DCA intervention group were intraperitoneally administered DCA with a loading dose of 80 mg/kg at 15 min after return of spontaneous circulation (ROSC), whereas rats in the Control group received equivalent volume of saline. DCA treatment increased 3-day survival time, and reduced neurologic deficit scores at 24, 48, and 72 h after ROSC. It also attenuated cellular apoptosis and neuronal damage in the hippocampal cornuammonis one region by hematoxylin-eosin staining and TdT-mediated dUTP nick-end labeling assay. In addition, DCA reduced the messenger RNA expression of tumor necrosis factor α and interleukin 1β in brain hippocampus and cortex after ROSC. Furthermore, DCA treatment significantly increased ATP production, PDH activity, and decreased blood glucose, lactate, and brain pyruvate levels after ROSC. Our results suggested that DCA has neuroprotective effects on brain injury after cardiac arrest, and its salutary effects were associated with an increase of mitochondrial energy metabolism in the brain through activation of PDH activity.