Brain Injury During CPR Prevented by Vascular Nitroxide

描述(由申请人提供)：经常伴随心脏骤停和复苏而来的脑损伤是毁灭性的。当在院前或非特殊护理医院环境中进行治疗时，只有不到10%的心肺复苏(CPR)尝试能够在没有脑损伤的情况下存活(Safar，1993)。我们提出了一种新的血管分区氮氧化物，多氮氧基白蛋白(PNA)，这是一种类似酶的抗氧化剂，可以减少CPR后的脑损伤。我们介绍了在CPR模型中的初步结果，显示PNA可以减轻大鼠心脏压迫和复苏后7天的CA1海马细胞损失。公布的结果也支持这一前提。在中风的大脑中动脉阻塞模型中，接受PNA治疗的小鼠显著免受神经损伤。 我们建议在CPR心脏按压模型中进一步建立PNA的脑保护作用。我们的具体目标是：1)解决PNA生产中的质量保证问题和体外疗效记录，以及2)比较PNA、人血清白蛋白(HSA)和生理盐水处理对海马体结构和功能的影响。第二个目标的终点将包括锥体细胞活性、NMDA受体1免疫反应性和海马片体外电生理学的测量。在全身缺血模型中，这种形态和电生理相结合的方法应该进一步证明PNA作为一种有效的神经保护剂的价值。这些目标的实现将满足在第二阶段SBIR赠款中进一步研究PNA的可行性要求，该阶段将强调剂量反应、延长的时间进程、神经恢复和PNA的治疗指数。

DESCRIPTION (provided by applicant): The brain damage that frequently accompanies cardiac arrest and resuscitation is devastating. Fewer than 10% of cardiopulmonary resuscitation (CPR) attempts result in survival without brain damage when treatment occurs in pre-hospital or a non-special care hospital environment (Safar, 1993). We propose that a novel vascular-compartmentalized nitroxide, polynitroxyl albumin (PNA), which is an enzyme-mimic antioxidant, can reduce brain damage after CPR. We present preliminary results in a CPR model showing PNA attenuates CA1 hippocampal cell loss 7 days after cardiac compression and resuscitation in rats. Published results also support this premise. In a middle cerebral artery occlusion model of stroke, mice treated with PNA were significantly protected against neural damage. We propose to further establish the cerebral protective activity of PNA in a cardiac compression model of CPR. Our specific aims are: 1) to address quality assurance issues in PNA production and in vitro documentation of efficacy, and 2) to compare the impact of PNA, human serum albumin (HSA) and saline treatment on the structure and function of the hippocampus. The end-points for the second aim will include measures of pyramidal cell viability, NMDA receptor 1 immunoreactivity, and in vitro electrophysiology of hippocampal slices. This combined morphological and electrophysiological approach in a whole body ischemia model should further document the value of PNA as a potent neuroprotectant. Attainment of these goals will fulfill the feasibility requirement for further study of PNA in a Phase II SBIR grant, which will emphasize dose response, extended time course, neurological recovery and the therapeutic index of PNA.