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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 organ. The objective of this study is to identify new putative mechanisms of neuroprotection elicited by remote ischemic femoral postconditioning. A 50% reduction in the infarct volume was observed when 100 min of middle cerebral artery occlusion was followed, 10 min later, by the remote postconditioning stimulus represented by 20 min of femoral artery occlusion. The use of in vivo silencing strategy allowed to demonstrate that NO production through nNOS mediates part of the neuroprotection. Indeed, whereas CNS nNOS expression was up-regulated by remote postconditioning, the pharmacological inhibition of nNOS or its silencing-mediated knocking-down partially prevented this neuroprotective effect. This nNOS overexpression 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 prevented when ganglion transmission was pharmacologically interrupted by hexamethonium, thus showing that neural factors are involved in this phenomenon.Collectively, the present study demonstrates that p-ERK and nNOS take part to the complex cascade of events triggered by ischemic remote postconditioning.

Substantial evidence has established that a short sub-lethal brain ischemia applied before a prolonged harmful ischemic episode confers ischemic neuroprotection, a phenomenon named ischemic preconditioning. Na+/Ca2+ exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, are plasmamembrane ionic transporters widely distributed in the brain, where they are involved in the control of Na+ and Ca2+ homeostasis and in the progression of stroke damage. The objective of this study was to evaluate the role of these three proteins in the preconditioning-induced neuroprotection.NCX protein expression was evaluated at different time points in the ischemic temporoparietal cortex of rats subjected to ischemia alone, to ischemic preconditioning alone, or to ischemic preconditioning plus ischemia.NCX1 and NCX3 were up-regulated in those brain regions protected by preconditioning treatment. These changes were mediated by p-AKT, since the p-AKT inhibition prevented the up-regulation of both isoforms. The relevant role of NCX1 and NCX3 during preconditioning was further confirmed when NCX1 and NCX3 silencing, induced by icv infusion of siRNA, partially reverted the preconditioning-induced neuroprotection.The enhancement of NCX1 and NCX3 expression and activity might represent a reasonable strategy to reduce the infarct extension after stroke.