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，少于10%的心肺复苏（CPR）尝试导致无脑损伤的存活率（Safar，1993）。我们提出一种新的血管区室化的氮氧化物，多硝酰白蛋白（PNA），这是一种酶模拟抗氧化剂，可以减少心肺复苏术后的脑损伤。我们目前的初步结果显示，在心肺复苏模型PNA减弱CA1海马细胞损失7天后，心脏按压和复苏大鼠。发表的结果也支持这一前提。在大脑中动脉闭塞中风模型中，用PNA治疗的小鼠显著地保护免受神经损伤。 我们建议进一步建立脑保护活性的PNA在心脏按压模型的CPR。我们的具体目标是：1）解决PNA生产中的质量保证问题和功效的体外记录，和2）比较PNA、人血清白蛋白（HSA）和盐水处理对海马结构和功能的影响。第二个目标的终点将包括锥体细胞活力，NMDA受体1免疫反应性和海马切片的体外电生理学的措施。这种在全身缺血模型中结合形态学和电生理学的方法应进一步证明PNA作为有效神经保护剂的价值。这些目标的实现将满足在第二阶段SBIR资助中进一步研究PNA的可行性要求，这将强调PNA的剂量反应、延长的时间过程、神经恢复和治疗指数。

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.