TY - JOUR
T1 - Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt
AU - Molinaro, Pasquale
AU - Sirabella, Rossana
AU - Pignataro, Giuseppe
AU - Petrozziello, Tiziana
AU - Secondo, Agnese
AU - Boscia, Francesca
AU - Vinciguerra, Antonio
AU - Cuomo, Ornella
AU - Philipson, Kenneth D.
AU - De Felice, Mario
AU - Di Lauro, Roberto
AU - Di Renzo, Gianfranco
AU - Annunziato, Lucio
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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.
KW - Akt
KW - Cre-LoxP
KW - Na-Ca exchanger
KW - NCX1
KW - stroke
UR - http://www.scopus.com/inward/record.url?scp=84989873930&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84989873930&partnerID=8YFLogxK
U2 - 10.1177/0271678X15611913
DO - 10.1177/0271678X15611913
M3 - Article
AN - SCOPUS:84989873930
VL - 36
SP - 1790
EP - 1803
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 10
ER -