title: Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt.
abstract: Three different Na+/Ca2+exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, are expressed in brain where they play a relevant role in maintaining Na+and Ca2+homeostasis. Although the neuroprotective roles of NCX2 and NCX3 in stroke have been elucidated, the relevance of NCX1 is still unknown because of embryonic lethality of its knocking-out, heart dysfunctions when it is overexpressed, and the lack of selectivity in currently available drugs. To overcome these limitations we generated two conditional genetically modified mice that upon tamoxifen administration showed a selective decrease or increase of NCX1 in cortical and hippocampal neurons. Interestingly, in cortex and hippocampus NCX1 overexpression increased, where NCX1 knock-out reduced, both exchanger activity and Akt1 phosphorylation, a neuronal survival signaling. More important, mice overexpressing NCX1 showed a reduced ischemic volume and an amelioration of focal and general deficits when subjected to transient middle cerebral artery occlusion. Conversely, NCX1-knock-out mice displayed a worsening of brain damage, focal and neurological deficits with a decrease in Akt phosphorylation. These results support the idea that NCX1 overexpression/activation may represent a feasible therapeutic opportunity in stroke intervention.
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Molinaro
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico SDN, Naples, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Sirabella
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pignataro
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Petrozziello
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Secondo
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Boscia
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vinciguerra
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Cuomo
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Philipson
authors.affiliation: Department of Molecular Medicine and Medical Biotechology, "Federico II" University of Naples, Naples, Italy IRGS, Biogem S.C.A.R.L., Ariano Irpino (AV), Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: De Felice
authors.affiliation: Department of Molecular Medicine and Medical Biotechology, "Federico II" University of Naples, Naples, Italy IRGS, Biogem S.C.A.R.L., Ariano Irpino (AV), Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Lauro
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Renzo
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy Istituto di Ricovero e Cura a Carattere Scientifico SDN, Naples, Italy lannunzi@unina.it.
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D055879:Gene Knock-In Techniques; D055786:Gene Knockout Techniques; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D020521:Stroke / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D013629:Tamoxifen; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Cre-LoxP; NCX1; Na+-Ca2+ exchanger; stroke