Postconditioning reduces ischemic damage after stroke in rats

描述（由申请人提供）：缺血预处理已被证明在致死性缺血之前给予可防止缺血性损伤，然而，只有在中风发生可预测的情况下，其在中风患者中的临床应用才有可能。脑卒中后的治疗策略对于治疗患者更为可行。脑卒中后的一个潜在目标是减少缺血后再灌注造成的损伤。改变心肌缺血时的再灌注已被证明可减小梗死面积。采用两种方法来改变再灌注：一种是控制血流的恢复，使再灌注逐渐增加；或者后处理，再灌注被中断几次。再灌注改变的概念尚未在卒中研究领域得到验证。因此，我们建议研究后处理或逐渐再灌注是否能减少脑卒中后的缺血性损伤。在我们的初步研究中，我们发现一种后处理模型减少了暂时性双侧颈总动脉（CCA）闭塞合并大脑中动脉（MCA）闭塞造成的局灶性缺血模型的损伤。后处理是通过释放和再闭塞cca在再灌注期间的一系列短暂中断来实现的。我们建议使用该模型进一步定义后条件反射的时间特征。此外，由于我们之前发现与完全再灌注相比，部分再灌注减少了梗死面积，我们将使用类似的局灶性缺血模型进一步确定渐进式再灌注是否也减少了缺血损伤。最后，我们建议研究脑卒中后适应的潜在神经保护机制。在心肌缺血中，后处理通过减少活性氧（ROS）产物和提高Akt活性而起到保护作用。由于这两者也会影响脑卒中和再灌注后的神经元死亡，因此我们建议研究后处理对脑卒中后ROS生成和Akt存活通路信号的影响。具体目标进一步定义后适应的时间特征，并探讨渐进式再灌注是否能减少缺血性梗死。具体目标2。目的：探讨局灶性缺血后，后处理或渐进式再灌注是否对神经功能有影响。具体目标3。探讨后处理的潜在神经保护机制，重点关注活性氧（ROS）的产生和Akt通路的活性。公共卫生相关性：脑卒中后的后处理可减少缺血性损伤，为脑卒中治疗的研究开辟了新的途径。后适应可能最终在临床上适用于脑卒中患者。

DESCRIPTION (provided by applicant): Ischemic preconditioning has been shown to protect against ischemic damage when given prior to a lethal ischemia, however, its clinical application for stroke patients is possible only when stroke occurrence is predictable. Post-stroke strategies are more feasible for treating patients. One potential post-stroke target is to reduce the damage caused by reperfusion after ischemia. Altering reperfusion in myocardial ischemia has been shown to reduce infract size. Two methods were employed to alter reperfusion: a controlled restoration of blood flow to give a gradual reperfusion; or postconditioning, where reperfusion is interrupted several times. This concept of altered reperfusion has not been tested in the field of stroke research. Thus, we propose to study whether postconditioning or gradual reperfusion reduces ischemic damage after stroke. In our pilot study we found that one model of postconditioning reduced damage in a model of focal ischemia generated by transient bilateral common carotid artery (CCA) occlusion combined with middle cerebral artery (MCA) occlusion. Postconditioning was achieved by a series of short interruptions during reperfusion by releasing and re-occluding the CCAs. We propose to further define the temporal characteristics for postconditioning using this model. In addition, since we previous found that partial reperfusion reduced infarct size compared with complete reperfusion, we will further determine if gradual reperfusion also reduces ischemic damage using a similar focal ischemia model. Finally, we propose to study the potential neuroprotective mechanisms of postconditioning after stroke. In myocardial ischemia, postconditioning was found to be protective by reducing products of reactive oxygen species (ROS) and improving Akt activity. Since both of these also influence neuronal death after stroke and reperfusion, we propose to study the effect of postconditioning on ROS generation and on signals of the Akt survival pathways after stroke. Specific Aim 1. To further define temporal characteristics for postconditioning and explore if gradual reperfusion reduces ischemic infarct. Specific Aim 2. To determine if postconditioning or gradual reperfusion spare neurological function after focal ischemia in rats. Specific Aim 3. To explore the potential neuroprotective mechanisms of postconditioning focusing on Reactive Oxygen Species (ROS) generation and Akt pathway activity. PUBLIC HEALTH RELEVANCE: Postconditioning after stroke reduces ischemic damage, opening up a new avenue for research for stroke treatment. Postconditioning may eventually be clinically applicable for stroke patients.