Treatment strategies in a rat model of cardiac arrest

心脏骤停大鼠模型的治疗策略

基本信息

批准号：
6906493
负责人：
Joseph Charles Lamanna
金额：
$ 36.34万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2007-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): A significant number of individuals die soon after a successful cardiopulmonary resuscitation form cardiac arrest, and of those that survive a significant fraction have residual neurological deficit. Most of the morbidity and mortality after initially successful resuscitation from cardiac arrest can be assigned to the immediate and delayed effects of reperfusion injury in the central nervous system. With aging, there is an increased incidence of cardiac arrest and subsequent death or residual neurological deficit secondary to reperfusion injury. This outcome is probably due to an increase in free radical production and decrease in defense mechanisms that exacerbates reperfusion injury in the aging. Nevertheless, the poor ability of the brain to recover from such reversible ischemic events remains, in all ages, unpromising and is most likely due to free radical damage and unstabilized energy metabolism. This project represents a new collaboration between investigators specializing in the area of reperfusion injury. We propose to investigate new treatment strategies aimed at using alternate energy substrates such as, pyruvate and ketones in combination with antioxidant type drugs, such as, melatonin, N-t-Butyl-a-Phenyl-nitrone, adenosine and methylisobutyl amiloride, as therapies for improving recovery from cardiac arrest. Novel esters will also be tested for their neuroprotective properties in brain against reperfusion injury. These compounds are unique in that they are metabolized to physiological substrates, such as, pyruvate, glycerol and N-acetylcyteine, and have shown to decrease the effects of reperfusion injury in other organ systems. An animal model of cardiac arrest and resuscitation, adult (3 mos) and aged (18 mos) rats will be used to test the efficacy of these new treatment strategies. One set of experimental protocols measures delayed loss of hippocampal CA1 neurons 4 and 30 days after cardiac arrest and resuscitation and survival rates. Another set of experimental protocols will elucidate specific mechanism(s) by which the selected energy substrates and agents and are effective.

描述（由申请人提供）：大量个体在成功进行心肺复苏后很快因心脏骤停而死亡，并且在存活下来的个体中，有很大一部分具有残留的神经功能缺损。心脏骤停最初成功复苏后的大部分发病率和死亡率可归因于中枢神经系统再灌注损伤的即时和延迟效应。随着年龄的增长，心脏骤停和随后的死亡或继发于再灌注损伤的残余神经功能缺损的发生率增加。这一结果可能是由于自由基产生的增加和防御机制的减少，从而加剧了衰老过程中的再灌注损伤。然而，在所有年龄段，大脑从这种可逆性缺血事件中恢复的能力都很差，这很可能是由于自由基损伤和不稳定的能量代谢造成的。该项目代表了再灌注损伤领域的研究人员之间的新合作。我们建议研究新的治疗策略，旨在使用替代能源底物（例如丙酮酸和酮）与抗氧化剂类型药物（例如褪黑激素、N-叔丁基-α-苯基硝酮、腺苷和甲基异丁基阿米洛利）相结合，作为改善病情的疗法从心脏骤停中恢复。还将测试新型酯在大脑中对抗再灌注损伤的神经保护特性。这些化合物的独特之处在于它们被代谢为生理底物，例如丙酮酸、甘油和N-乙酰半胱氨酸，并且已被证明可以减少其他器官系统再灌注损伤的影响。心脏骤停和复苏的动物模型、成年（3个月）和老年（18个月）大鼠将用于测试这些新治疗策略的功效。一组实验方案测量心脏骤停和复苏后 4 天和 30 天海马 CA1 神经元的延迟损失以及存活率。另一组实验方案将阐明所选能量底物和试剂有效的具体机制。