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，只有当卒中发生可预测时，才可能将其用于卒中患者的临床应用。卒中后策略对于治疗患者更可行。一个潜在的中风后目标是减少缺血后再灌注引起的损伤。改变心肌缺血的再灌注已被证明可以减少梗死面积。采用两种方法来改变再灌注：一种是控制血流的恢复，以提供逐渐的再灌注;另一种是后处理，其中再灌注中断数次。这种改变再灌注的概念尚未在中风研究领域得到验证。因此，我们建议研究是否后处理或逐渐再灌注减少中风后的缺血性损伤。在我们的初步研究中，我们发现一种后处理模型减少了短暂双侧颈总动脉（CCA）闭塞结合大脑中动脉（MCA）闭塞产生的局灶性缺血模型中的损伤。后处理通过在再灌注期间释放和重新闭塞CCA的一系列短暂中断来实现。我们建议使用这个模型来进一步定义后处理的时间特征。此外，由于我们先前发现与完全再灌注相比，部分再灌注减少了梗死面积，因此我们将使用类似的局灶性缺血模型进一步确定逐渐再灌注是否也减少了缺血性损伤。最后，我们建议研究脑卒中后处理的潜在神经保护机制。在心肌缺血中，后处理被发现是通过减少活性氧（ROS）的产物和提高Akt活性的保护。由于这两个也影响中风和再灌注后的神经元死亡，我们建议研究后处理对ROS的产生和中风后Akt生存途径的信号的影响。具体目标1。进一步确定后处理的时间特征，并探索渐进再灌注是否减少缺血性梗死。具体目标2。目的：探讨大鼠局灶性脑缺血后，后处理或逐渐再灌注是否能保护神经功能。具体目标3。探讨后处理对神经元保护作用的可能机制，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：中风后的后适应可减少缺血性损伤，为中风治疗研究开辟了新途径。后处理可能最终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.