Postconditioning reduces ischemic damage after stroke in rats

描述(由申请人提供)：缺血预适应已被证明在致命性缺血之前应用可防止缺血损伤，然而，只有在中风发生可预测的情况下，其临床应用才有可能。卒中后的治疗策略对患者来说更可行。卒中后的一个潜在目标是减少缺血后再灌注造成的损害。在心肌缺血时改变再灌流已被证明可以减少梗塞面积。采用两种方法改变再灌流：控制血流恢复以实现逐渐再灌流；或后处理，再灌流被多次中断。这种改变再灌流的概念还没有在卒中研究领域中得到验证。因此，我们建议研究后处理或逐渐再灌流是否能减少卒中后的缺血性损伤。在我们的先导性研究中，我们发现一种后处理模型减少了由短暂的双侧颈总动脉(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害。后处理是在再灌注期间通过释放和重新闭塞颈总动脉进行一系列短暂的中断来实现的。我们建议使用该模型进一步定义后处理的时间特性。此外，由于我们先前发现部分再灌注与完全再灌注相比缩小了梗塞面积，我们将使用类似的局灶性缺血模型进一步确定逐步再灌注是否也能减少缺血损伤。最后，我们建议研究卒中后适应的潜在神经保护机制。在心肌缺血时，后处理被发现通过减少ROS产物和提高Akt活性而起到保护作用。由于这两者也影响卒中后和再灌流后神经元的死亡，我们建议研究后处理对卒中后ROS产生和Akt生存通路信号的影响。具体目的1.进一步明确后处理的时间特征，并探讨渐进性再灌流是否能减少缺血性脑梗塞。具体目的2.确定大鼠局灶性脑缺血后后处理或渐进性再灌流是否对神经功能有保护作用。具体目的3.探讨后处理对脑内ROS生成和Akt通路活性的潜在神经保护作用机制。公共卫生相关性：中风后的后处理减少了缺血性损害，为中风治疗的研究开辟了一条新的途径。后处理最终可能在临床上适用于中风患者。

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.