title: NCX as a key player in the neuroprotection exerted by ischemic preconditioning and postconditioning.
abstract: Ischemic preconditioning is a neuroprotective mechanism in which a brief non-injurious episode of ischemia protects the brain from a subsequent lethal insult. Recently, it has been reported that modified reperfusion subsequent to a prolonged ischemic episode may also confer neuroprotection, a phenomenon termed postconditioning. Mitogen-activated protein kinases (MAPK) play a key role in these two neuroprotective mechanisms. The aim of this study was to evaluate whether Na(+)/Ca(2+) exchangers (NCXs), a family of ionic transporters that contribute to the maintenance of intracellular ionic homeostasis, contribute to the neuroprotection elicited by ischemic preconditioning and postconditioning.Results of this study indicated that (1) NCX1 and NCX3 are upregulated in those brain regions protected by preconditioning, while (2) postconditioning treatment induces an upregulation only in NCX3 expression. (3) NCX1 upregulation and NCX3 upregulation are mediated by p-AKT since its inhibition reverted the neuroprotective effect of preconditioning and postconditioning and prevented NCXs overexpression. (4) The involvement of NCX in preconditioning and postconditioning neuroprotection is further supported by the results of experiments showing that a partial reversion of the protective effect induced by preconditioning was obtained by silencing NCX1 or NCX3, while the silencing of NCX3 was able to mitigate the protection induced by ischemic postconditioning.Altogether, the data presented here suggest that NCX1 and NCX3 -represent two promising druggable targets for setting on new strategies in stroke therapy.
authors.affiliation: Department Neuroscience, Federico II University of Naples, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pignataro
authors.forename: Ornella
authors.initials: O
authors.lastname: Cuomo
authors.forename: Antonio
authors.initials: A
authors.lastname: Vinciguerra
authors.forename: Rossana
authors.initials: R
authors.lastname: Sirabella
authors.forename: Elga
authors.initials: E
authors.lastname: Esposito
authors.forename: Francesca
authors.initials: F
authors.lastname: Boscia
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Renzo
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019194:Ischemic Preconditioning; D020935:MAP Kinase Signaling System / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; C101832:SLC38A3 protein, human; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases