Transient limb ischemia induces remote postconditioning and protects the brain from stroke induced damage

ABSTRACT Background. It has been recently hypothesized that a sub-lethal ischemic insult induced in an organ is able to protect from a harmful ischemia occurring in a different and anatomically distant organ. In this paper, a new neuroprotective strategy termed remote ischemic postconditioning is described and characterized for the first time. This neuroprotective mechanism occurs in rats in which a harmful brain ischemia is followed by a sub-lethal ischemic insult applied at the femoral artery level. Methods and Results. Remote ischemic postconditioning was induced in adult male rats by subjecting them to 100 minutes of middle cerebral artery occlusion (MCAO) followed by several brief cycles of ipsilateral femoral artery occlusion-reperfusion. Within all the considered experimental protocols, the one in which 100 minutes of MCAO were followed by 10 minutes reperfusion and 20 minutes occlusion of the femoral artery was the most effective in reducing brain infarct, resulting in almost 50% reduction in the infarct volume if compared to animals subjected to 100' MCAO alone. Importantly, this protection was still present 7 days after remote postconditioning induction. Experiments carried out with specific inhibitors of each NO synthesizing enzyme, demonstrated that NO production through nNOS mediates part of the neuroprotective effect induced by remote ischemic postconditioning. In fact, the pharmacological blockade of nNOS was able to partially revert the neuroprotection induced by remote postconditioning. In addition, the neuroprotection induced by remote postconditioning was partially reverted when ganglion transmission was pharmacologically interrupted by hxamethonium, thus showing that neural factors are involved in this neuroprotective process. Conclusion. Collectively, the results of the present study demonstrate that remote postconditioning induces a marked neuroprotection through nNOS activation and it may represent a new clinically feasible therapeutic approach to treat ischemic stroke.