Abstract 95: Remote Postconditioning Protects Ischemic Brain by nNOS and p-ERK Activation
Objective: It has recently been hypothesized that a sub-lethal ischemic insult induced in one organ is able to protect from a harmful ischemia occurring in a different and anatomically distant organ. Objective of this study is to characterize remote ischemic femoral postconditioning as a new method to induce post-ischemic brain neuroprotection
Methods and Results: Remote ischemic postconditioning was induced in adult rats by 100 minutes of middle cerebral artery occlusion (tMCAO) followed by several cycles of femoral artery occlusion-reperfusion. One hundred minutes of tMCAO followed, 10 minutes later, by 20 minutes of femoral artery occlusion effectively reduced cerebral infarct volume by 50%.Importantly, this protection was still present 7 days after remote postconditioning. Furthermore, the use of in vivo silencing strategy allowed to demonstrate that NO production through nNOS mediates part of the neuroprotection induced by remote ischemic postconditioning. Indeed, whereas CNS nNOS expression was up-regulated by remote postconditioning, the pharmacological inhibition of nNOS or its silencing-mediated knocking-down partially reverted this neuroprotective effect. This nNOS overexpression and activity seemed to be p-ERK dependent. In fact, p-ERK expression increased in brain cortex after remote postconditioning, and its pharmacological inhibition prevented both nNOS overexpression and remote postconditioning-mediated neuroprotection. Interestingly, neuroprotection induced by remote postconditioning was partially reverted when ganglion transmission was pharmacologically interrupted by hexamethonium, thus showing that neural factors are involved in this phenomenon.
Interpretation: Collectively, the results of the present study demonstrate that remote postconditioning induces a marked neuroprotection through p-ERK/nNOS, neuronally-mediated activation, and may represent a new clinically feasible therapeutic approach to treat ischemic stroke.
- © 2012 by American Heart Association, Inc.