Treatment strategies in a rat model of cardiac arrest

心脏骤停大鼠模型的治疗策略

• 批准号: 6666676
• 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
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6666676
• 关键词: adenosine; age difference; amiloride; animal old age; antioxidants; bioenergetics; brain disorder chemotherapy; cardiopulmonary resuscitation; cerebral ischemia /hypoxia; disease /disorder model; drug screening /evaluation; heart arrest; laboratory rat; mature animal; melatonin; neuroprotectants; nonhuman therapy evaluation; oxidative stress; pyruvates; reperfusion

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）：在成功的心肺复苏形成心脏骤停后不久，大量个体死亡，而在大量部分中存活的人则具有残留的神经系统缺陷。 最初从心脏骤停复苏后，大多数发病率和死亡率都可以分配给中枢神经系统中再灌注损伤的直接和延迟影响。 随着衰老，心脏骤停和随后的死亡或继发性损伤的残留神经缺陷的发生率增加。 这种结果可能是由于自由基生产的增加以及加剧衰老中再灌注损伤的防御机制的减少。 然而，在所有年龄段的人中，大脑从这种可逆的缺血事件中恢复的能力差，很可能是由于自由基损害和无稳定的能量代谢所致。 该项目代表了专门研究再灌注损伤领域的调查人员之间的新合作。 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. 新型酯还将测试其在大脑中针对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-乙酰基丝氨酸，并已证明可以减少再灌注损伤对其他器官系统的影响。 心脏骤停和复苏的动物模型，成人（3个MO）和年龄（18 MOS）大鼠将用于测试这些新治疗策略的功效。 一组实验方案测量了心脏骤停和复苏和生存率后4和30天延迟海马CA1神经元的损失。 另一组实验方案将阐明所选能量底物和试剂并有效的特定机制。