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The Journal of Neuroscience, January 30, 2008, 28(5):1179-1184; doi:10.1523/JNEUROSCI.4671-07.2008

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Neurobiology of Disease
Targeted Disruption of Na⁺/Ca²⁺ Exchanger 3 (NCX3) Gene Leads to a Worsening of Ischemic Brain Damage

Pasquale Molinaro,^1 * Ornella Cuomo,^1 * Giuseppe Pignataro,^1 * Francesca Boscia,^1 * Rossana Sirabella,¹ Anna Pannaccione,¹ Agnese Secondo,¹ Antonella Scorziello,¹ Annagrazia Adornetto,¹ Rosaria Gala,¹ Davide Viggiano,¹ Sophie Sokolow,² Andre Herchuelz,² Stèphane Schurmans,³ Gianfranco Di Renzo,¹ and Lucio Annunziato¹

¹Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, 80131 Naples, Italy, ²Laboratory of Pharmacology and Therapeutics, and ³Institut de Recherches en Biologie Humaine et Moléculaire-Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, 6041 Gosselies, Belgium

Correspondence should be addressed to Dr. Lucio Annunziato, Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, Via Pansini 5, 80131 Naples, Italy. Email: lannunzi{at}unina.it

Na⁺/Ca²⁺ exchanger 3 (NCX3), one of the three isoforms of the NCX family, is highly expressed in the brain and is involved in the maintenance of intracellular Na⁺ and Ca²⁺ homeostasis. Interestingly, whereas the function of NCX3 under physiological conditions has been determined, its role under anoxia is still unknown. To assess NCX3 role in cerebral ischemia, we exposed ncx3–/– mice to transient middle cerebral artery occlusion followed by reperfusion. In addition, to evaluate the effect of ncx3 ablation on neuronal survival, organotypic hippocampal cultures and primary cortical neurons from ncx3–/– mice were subjected to oxygen glucose deprivation (OGD) plus reoxygenation. Here we report that ncx3 gene suppression leads to a worsening of brain damage after focal ischemia and to a massive neuronal death in all the hippocampal fields of organotypic cultures as well as in cortical neurons from ncx3–/– mice exposed to OGD plus reoxygenation. In addition, in ncx3–/– cortical neurons exposed to hypoxia, NCX currents, recorded in the reverse mode of operation, were significantly lower than those detected in ncx3+/+. From these results, NCX3 protein emerges as a new molecular target that may have a potential therapeutic value in modulating cerebral ischemia.

Key words: NCX; MCAO; cerebral ischemia; sodium calcium exchanger; OGD; organotypic hippocampal cultures

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Received July 6, 2007; revised Dec. 5, 2007; accepted Dec. 6, 2007.

Correspondence should be addressed to Dr. Lucio Annunziato, Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, Via Pansini 5, 80131 Naples, Italy. Email: lannunzi{at}unina.it

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