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Does Na+/Ca2+ Exchanger, NCX, Represent a New Druggable Target in Stroke Intervention?

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Abstract

Stroke causes a rapid cell death in the core of the injured region and triggers mechanisms in surrounding penumbra area that leads to changes in concentrations of several ions like intracellular Ca2+, Na+, H+, K+, and radicals such as reactive oxygen species and reactive nitrogen species. When a dysregulation of homeostasis of these messengers occurs, it can trigger cell death. In particular, it is widely accepted that a critical factor in determining neuronal death during cerebral ischemia is progressive dysregulation of Ca2+, Na+, K+, and H+ homeostasis that activate several death pathways, including oxidative and nitrosative stress, mitochondrial dysfunction, protease activation, and apoptosis. In the last decade, several seminal experimental works are markedly changing the scenario of research of principal players of an ischemic event. Indeed, some plasma membrane channels and transporters, involved in the control of Ca2+, Na+, K+, and H+ ion influx or efflux and, therefore, responsible for maintaining the homeostasis of these four cations, might function as crucial players in initiation of brain ischemic process. Indeed, these proteins, by regulating ionic homeostasis, may provide the molecular basis underlying glutamate-independent Ca2+ and Na+ overload mechanisms in neuronal ischemic cell death and, most importantly, may represent more suitable molecular targets for therapeutic intervention. Recently, a great deal of interest has been devoted to clarify the role of the plasma membrane protein known as Na+/Ca2+ exchanger, a transporter able to control Na+ and Ca2+ homeostasis. In this review, the pathophysiological role of NCX and its implication as a potential target in stroke intervention will be examined.

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References

  1. Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet. 2008;371:1612–23.

    Article  CAS  PubMed  Google Scholar 

  2. Annunziato L, Cataldi M, Pignataro G, Secondo A, Molinaro P. Glutamate-independent calcium toxicity: introduction. Stroke. 2007;38:661–4.

    Article  PubMed  Google Scholar 

  3. Annunziato L, Pignataro G, Boscia F, Sirabella R, Formisano L, Saggese M, et al. Di Renzo GF: ncx1, ncx2, and ncx3 gene product expression and function in neuronal anoxia and brain ischemia. Ann N Y Acad Sci. 2007;1099:413–26.

    Article  CAS  PubMed  Google Scholar 

  4. Olney JW. Status of monosodium glutamate revisited. Am J Clin Nutr. 1973;26:683–5.

    CAS  PubMed  Google Scholar 

  5. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22:391–7.

    Article  CAS  PubMed  Google Scholar 

  6. Haddad GG, Jiang C. O2-sensing mechanisms in excitable cells: role of plasma membrane K+ channels. Annu Rev Physiol. 1997;59:23–42.

    Article  CAS  PubMed  Google Scholar 

  7. Annunziato L, Pignataro G, Di Renzo GF. Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol Rev. 2004;56:633–54.

    Article  CAS  PubMed  Google Scholar 

  8. Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988;1:623–34.

    Article  CAS  PubMed  Google Scholar 

  9. Choi DW. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci. 1988;11:465–9.

    Article  CAS  PubMed  Google Scholar 

  10. Choi DW, Koh JY, Peters S. Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J Neurosci. 1988;8:185–96.

    CAS  PubMed  Google Scholar 

  11. Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999;79:1431–568.

    CAS  PubMed  Google Scholar 

  12. Blaustein MP, Lederer WJ. Sodium/calcium exchange: its physiological implications. Physiol Rev. 1999;79:763–854.

    CAS  PubMed  Google Scholar 

  13. Reeves JP, Hale CC. The stoichiometry of the cardiac sodium–calcium exchange system. J Biol Chem. 1984;259:7733–9.

    CAS  PubMed  Google Scholar 

  14. Hilgemann DW. New insights into the molecular and cellular workings of the cardiac Na+/Ca2+ exchanger. Am J Physiol Cell Physiol. 2004;287:C1167–1172.

    Article  CAS  PubMed  Google Scholar 

  15. Kang TM, Hilgemann DW. Multiple transport modes of the cardiac Na+/Ca2+ exchanger. Nature. 2004;427:544–8.

    Article  CAS  PubMed  Google Scholar 

  16. Nicoll DA, Longoni S, Philipson KD. Molecular cloning and functional expression of the cardiac sarcolemmal Na(+)–Ca2+ exchanger. Science. 1990;250:562–5.

    Article  CAS  PubMed  Google Scholar 

  17. Li Z, Matsuoka S, Hryshko LV, Nicoll DA, Bersohn MM, Burke EP, et al. Cloning of the NCX2 isoform of the plasma membrane Na(+)–Ca2+ exchanger. J Biol Chem. 1994;269:17434–9.

    CAS  PubMed  Google Scholar 

  18. Nicoll DA, Quednau BD, Qui Z, Xia YR, Lusis AJ, Philipson KD. Cloning of a third mammalian Na+–Ca2+ exchanger, NCX3. J Biol Chem. 1996;271:24914–21.

    Article  CAS  PubMed  Google Scholar 

  19. Quednau BD, Nicoll DA, Philipson KD. Tissue specificity and alternative splicing of the Na+/Ca2+ exchanger isoforms NCX1, NCX2, and NCX3 in rat. Am J Physiol. 1997;272:C1250–1261.

    CAS  PubMed  Google Scholar 

  20. Nicoll DA, Ottolia M, Lu L, Lu Y, Philipson KD. A new topological model of the cardiac sarcolemmal Na+–Ca2+ exchanger. J Biol Chem. 1999;274:910–7.

    Article  CAS  PubMed  Google Scholar 

  21. Philipson KD, Nicoll DA. Sodium–calcium exchange: a molecular perspective. Annu Rev Physiol. 2000;62:111–33.

    Article  CAS  PubMed  Google Scholar 

  22. Lee SL, Yu AS, Lytton J. Tissue-specific expression of Na(+)–Ca2+ exchanger isoforms. J Biol Chem. 1994;269:14849–52.

    CAS  PubMed  Google Scholar 

  23. Endo H, Nito C, Kamada H, Yu F, Chan PH. Akt/GSK3beta survival signaling is involved in acute brain injury after subarachnoid hemorrhage in rats. Stroke. 2006;37:2140–6.

    Article  CAS  PubMed  Google Scholar 

  24. Canitano A, Papa M, Boscia F, Castaldo P, Sellitti S, Taglialatela M, et al. Brain distribution of the Na+/Ca2+ exchanger-encoding genes NCX1, NCX2, and NCX3 and their related proteins in the central nervous system. Ann N Y Acad Sci. 2002;976:394–404.

    Article  CAS  PubMed  Google Scholar 

  25. Madison DV, Schuman EM. LTP, post or pre? A look at the evidence for the locus of long-term potentiation. New Biol. 1991;3:549–57.

    CAS  PubMed  Google Scholar 

  26. Juhaszova M, Shimizu H, Borin ML, Yip RK, Santiago EM, Lindenmayer GE, et al. Localization of the Na(+)–Ca2+ exchanger in vascular smooth muscle, and in neurons and astrocytes. Ann N Y Acad Sci. 1996;779:318–35.

    Article  CAS  PubMed  Google Scholar 

  27. Arita J, Kimura F. In vitro dopamine biosynthesis in the median eminence of rat hypothalamic slices: possible involvement of a Na+–Ca2+ exchange mechanism. Brain Res. 1985;338:384–6.

    Article  CAS  PubMed  Google Scholar 

  28. Taglialatela M, Amoroso S, Canzoniero LM, Di Renzo GF, Annunziato L. Membrane events and ionic processes involved in dopamine release from tuberoinfundibular neurons. II. Effect of the inhibition of the Na+–Ca++ exchange by amiloride. J Pharmacol Exp Ther. 1988;246:689–94.

    CAS  PubMed  Google Scholar 

  29. Taglialatela M, Amoroso S, Kaparos G, Maurano F, Di Renzo GF, Annunziato L. Membrane events and ionic processes involved in dopamine release from tuberoinfundibular neurons. I. Effect of the inhibition of the Na+, K + -adenosine triphosphatase pump by ouabain. J Pharmacol Exp Ther. 1988;246:682–8.

    CAS  PubMed  Google Scholar 

  30. Annunziato L, Taglialatela M, Canzoniero LM, Fatatis A, Di Rienzo G. The Na(+)-Ca++ exchanger in central nerve endings: the relationship between its pharmacological blockade and dopamine release from tuberoinfundibular hypothalamic neurons. Neurochem Int. 1992;20(Suppl):95S–9S.

    Article  CAS  PubMed  Google Scholar 

  31. Taglialatela M, Canzoniero LM, Cragoe Jr EJ, Di Renzo G, Annunziato L. Na(+)–Ca2+ exchange activity in central nerve endings. II. Relationship between pharmacological blockade by amiloride analogues and dopamine release from tuberoinfundibular hypothalamic neurons. Mol Pharmacol. 1990;38:393–400.

    CAS  PubMed  Google Scholar 

  32. Taglialatela M, Di Renzo G, Annunziato L. Na(+)–Ca2+ exchange activity in central nerve endings. I. Ionic conditions that discriminate 45Ca2+ uptake through the exchanger from that occurring through voltage-operated Ca2+ channels. Mol Pharmacol. 1990;38:385–92.

    CAS  PubMed  Google Scholar 

  33. Magyar K, Nguyen TT, Torok TL. Toth PT: [3H]noradrenaline release from rabbit pulmonary artery: sodium-pump-dependent sodium–calcium exchange. J Physiol. 1987;393:29–42.

    CAS  PubMed  Google Scholar 

  34. Di Renzo G, Amoroso S, Bassi A, Fatatis A, Cataldi M, Colao AM, et al. Role of the Na(+)–Ca2+ and Na(+)–H+ antiporters in prolactin release from anterior pituitary cells in primary culture. Eur J Pharmacol. 1995;294:11–5.

    Article  PubMed  Google Scholar 

  35. Eriksson KS, Stevens DR, Haas HL. Serotonin excites tuberomammillary neurons by activation of Na(+)/Ca(2+)-exchange. Neuropharmacology. 2001;40:345–51.

    Article  CAS  PubMed  Google Scholar 

  36. Sergeeva OA, Amberger BT, Eriksson KS, Scherer A, Haas HL. Co-ordinated expression of 5-HT2C receptors with the NCX1 Na+/Ca2+ exchanger in histaminergic neurones. J Neurochem. 2003;87:657–64.

    Article  CAS  PubMed  Google Scholar 

  37. Jeon D, Yang YM, Jeong MJ, Philipson KD, Rhim H, Shin HS. Enhanced learning and memory in mice lacking Na+/Ca2+ exchanger 2. Neuron. 2003;38:965–76.

    Article  CAS  PubMed  Google Scholar 

  38. Sokolow S, Manto M, Gailly P, Molgo J, Vandebrouck C, Vanderwinden JM, et al. Impaired neuromuscular transmission and skeletal muscle fiber necrosis in mice lacking Na/Ca exchanger 3. J Clin Invest. 2004;113:265–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Molinaro P, Cataldi M, Cuomo O, Viggiano D, Pignataro G, Sirabella R, et al. Genetically modified mice as a strategy to unravel the role played by the Na(+)/Ca (2+) exchanger in brain ischemia and in spatial learning and memory deficits. Adv Exp Med Biol. 2013;961:213–22.

    Article  CAS  PubMed  Google Scholar 

  40. Molinaro P, Viggiano D, Nistico R, Sirabella R, Secondo A, Boscia F, et al. Na+–Ca2+ exchanger (NCX3) knock-out mice display an impairment in hippocampal long-term potentiation and spatial learning and memory. J Neurosci. 2011;31:7312–21.

    Article  CAS  PubMed  Google Scholar 

  41. Kintner DB, Wang Y, Sun D. Role of membrane ion transport proteins in cerebral ischemic damage. Front Biosci. 2007;12:762–70.

    Article  CAS  PubMed  Google Scholar 

  42. Boscia F, Gala R, Pannaccione A, Secondo A, Scorziello A, Di Renzo G, et al. NCX1 expression and functional activity increase in microglia invading the infarct core. Stroke. 2009;40:3608–17.

    Article  CAS  PubMed  Google Scholar 

  43. Amoroso S, De Maio M, Russo GM, Catalano A, Bassi A, Montagnani S, et al. Pharmacological evidence that the activation of the Na(+)–Ca2+ exchanger protects C6 glioma cells during chemical hypoxia. Br J Pharmacol. 1997;121:303–9.

    Article  CAS  PubMed  Google Scholar 

  44. Amoroso S, Tortiglione A, Secondo A, Catalano A, Montagnani S, Di Renzo G, et al. Sodium nitroprusside prevents chemical hypoxia-induced cell death through iron ions stimulating the activity of the Na+–Ca2+ exchanger in C6 glioma cells. J Neurochem. 2000;74:1505–13.

    Article  CAS  PubMed  Google Scholar 

  45. Matsuda T, Arakawa N, Takuma K, Kishida Y, Kawasaki Y, Sakaue M, et al. SEA0400, a novel and selective inhibitor of the Na+–Ca2+ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. J Pharmacol Exp Ther. 2001;298:249–56.

    CAS  PubMed  Google Scholar 

  46. Matsuda T, Takuma K, Nishiguchi E, Hashimoto H, Azuma J, Baba A. Involvement of Na+–Ca2+ exchanger in reperfusion-induced delayed cell death of cultured rat astrocytes. Eur J Neurosci. 1996;8:951–8.

    Article  CAS  PubMed  Google Scholar 

  47. Andreeva N, Khodorov B, Stelmashook E, Cragoe Jr E, Victorov I. Inhibition of Na+/Ca2+ exchange enhances delayed neuronal death elicited by glutamate in cerebellar granule cell cultures. Brain Res. 1991;548:322–5.

    Article  CAS  PubMed  Google Scholar 

  48. Kiedrowski L. N-Methyl-d-aspartate excitotoxicity: relationships among plasma membrane potential, Na(+)/Ca(2+) exchange, mitochondrial Ca(2+) overload, and cytoplasmic concentrations of Ca(2+), H(+), and K(+). Mol Pharmacol. 1999;56:619–32.

    CAS  PubMed  Google Scholar 

  49. Czyz A, Baranauskas G, Kiedrowski L. Instrumental role of Na+ in NMDA excitotoxicity in glucose-deprived and depolarized cerebellar granule cells. J Neurochem. 2002;81:379–89.

    Article  CAS  PubMed  Google Scholar 

  50. Schroder UH, Breder J, Sabelhaus CF, Reymann KG. The novel Na+/Ca2+ exchange inhibitor KB-R7943 protects CA1 neurons in rat hippocampal slices against hypoxic/hypoglycemic injury. Neuropharmacology. 1999;38:319–21.

    Article  CAS  PubMed  Google Scholar 

  51. Stys PK, Lopachin RM. Mechanisms of calcium and sodium fluxes in anoxic myelinated central nervous system axons. Neuroscience. 1998;82:21–32.

    Article  CAS  PubMed  Google Scholar 

  52. Stys PK, Ransom BR, Waxman SG, Davis PK. Role of extracellular calcium in anoxic injury of mammalian central white matter. Proc Natl Acad Sci U S A. 1990;87:4212–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Li S, Jiang Q, Stys PK. Important role of reverse Na(+)–Ca(2+) exchange in spinal cord white matter injury at physiological temperature. J Neurophysiol. 2000;84:1116–9.

    CAS  PubMed  Google Scholar 

  54. Wolf JA, Stys PK, Lusardi T, Meaney D, Smith DH. Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels. J Neurosci. 2001;21:1923–30.

    CAS  PubMed  Google Scholar 

  55. Annunziato L, Pannaccione A, Cataldi M, Secondo A, Castaldo P, Di Renzo G, et al. Modulation of ion channels by reactive oxygen and nitrogen species: a pathophysiological role in brain aging? Neurobiol Aging. 2002;23:819–34.

    Article  CAS  PubMed  Google Scholar 

  56. Michaelis ML, Johe K, Kitos TE. Age-dependent alterations in synaptic membrane systems for Ca2+ regulation. Mech Ageing Dev. 1984;25:215–25.

    Article  CAS  PubMed  Google Scholar 

  57. Canzoniero LM, Rossi A, Taglialatela M, Amoroso S, Annunziato L, Di Renzo G. The Na(+)–Ca2+ exchanger activity in cerebrocortical nerve endings is reduced in old compared to young and mature rats when it operates as a Ca2+ influx or efflux pathway. Biochim Biophys Acta. 1992;1107:175–8.

    Article  CAS  PubMed  Google Scholar 

  58. Michaelis ML. Ca2+ handling systems and neuronal aging. Ann N Y Acad Sci. 1989;568:89–94.

    Article  CAS  PubMed  Google Scholar 

  59. Weiss JH, Pike CJ, Cotman CW. Ca2+ channel blockers attenuate beta-amyloid peptide toxicity to cortical neurons in culture. J Neurochem. 1994;62:372–5.

    Article  CAS  PubMed  Google Scholar 

  60. Mattson MP, Barger SW, Cheng B, Lieberburg I, Smith-Swintosky VL. Rydel RE: beta-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer's disease. Trends Neurosci. 1993;16:409–14.

    Article  CAS  PubMed  Google Scholar 

  61. Furukawa K, Mattson MP. Cytochalasins protect hippocampal neurons against amyloid beta-peptide toxicity: evidence that actin depolymerization suppresses Ca2+ influx. J Neurochem. 1995;65:1061–8.

    Article  CAS  PubMed  Google Scholar 

  62. Wu A, Derrico CA, Hatem L, Colvin RA. Alzheimer's amyloid-beta peptide inhibits sodium/calcium exchange measured in rat and human brain plasma membrane vesicles. Neuroscience. 1997;80:675–84.

    Article  CAS  PubMed  Google Scholar 

  63. Pannaccione A, Secondo A, Molinaro P, D'Avanzo C, Cantile M, Esposito A, et al. A new concept: Abeta1-42 generates a hyperfunctional proteolytic NCX3 fragment that delays caspase-12 activation and neuronal death. J Neurosci. 2012;32:10609–17.

    Article  CAS  PubMed  Google Scholar 

  64. Boscia F, Gala R, Pignataro G, de Bartolomeis A, Cicale M, Ambesi-Impiombato A, et al. Permanent focal brain ischemia induces isoform-dependent changes in the pattern of Na+/Ca2+ exchanger gene expression in the ischemic core, periinfarct area, and intact brain regions. J Cereb Blood Flow Metab. 2006;26:502–17.

    Article  CAS  PubMed  Google Scholar 

  65. Pignataro G, Gala R, Cuomo O, Tortiglione A, Giaccio L, Castaldo P, et al. Two sodium/calcium exchanger gene products, NCX1 and NCX3, play a major role in the development of permanent focal cerebral ischemia. Stroke. 2004;35:2566–70.

    Article  CAS  PubMed  Google Scholar 

  66. Molinaro P, Cuomo O, Pignataro G, Boscia F, Sirabella R, Pannaccione A, et al. Targeted disruption of Na+/Ca2+ exchanger 3 (NCX3) gene leads to a worsening of ischemic brain damage. J Neurosci. 2008;28:1179–84.

    Article  CAS  PubMed  Google Scholar 

  67. Linck B, Qiu Z, He Z, Tong Q, Hilgemann DW, Philipson KD. Functional comparison of the three isoforms of the Na+/Ca2+ exchanger (NCX1, NCX2, NCX3). Am J Physiol. 1998;274:C415–423.

    CAS  PubMed  Google Scholar 

  68. Secondo A, Staiano RI, Scorziello A, Sirabella R, Boscia F, Adornetto A, et al. BHK cells transfected with NCX3 are more resistant to hypoxia followed by reoxygenation than those transfected with NCX1 and NCX2: possible relationship with mitochondrial membrane potential. Cell Calcium. 2007;42:521–35.

    Article  CAS  PubMed  Google Scholar 

  69. Condrescu M, Gardner JP, Chernaya G, Aceto JF, Kroupis C, Reeves JP. ATP-dependent regulation of sodium–calcium exchange in Chinese hamster ovary cells transfected with the bovine cardiac sodium–calcium exchanger. J Biol Chem. 1995;270:9137–46.

    Article  CAS  PubMed  Google Scholar 

  70. Sirabella R, Secondo A, Pannaccione A, Scorziello A, Valsecchi V, Adornetto A, et al. Anoxia-induced NF-kappaB-dependent upregulation of NCX1 contributes to Ca2+ refilling into endoplasmic reticulum in cortical neurons. Stroke. 2009;40:922–9.

    Article  CAS  PubMed  Google Scholar 

  71. Pignataro G, Tortiglione A, Scorziello A, Giaccio L, Secondo A, Severino B, et al. Evidence for a protective role played by the Na+/Ca2+ exchanger in cerebral ischemia induced by middle cerebral artery occlusion in male rats. Neuropharmacology. 2004;46:439–48.

    Article  CAS  PubMed  Google Scholar 

  72. Molinaro P, Cantile M, Cuomo O, Secondo A, Pannaccione A, Ambrosino P, et al. Neurounina-1, a novel compound that increases Na+/Ca2+ exchanger activity, effectively protects against stroke damage. Mol Pharmacol. 2012;83:142–56.

    Article  PubMed  Google Scholar 

  73. Formisano L, Guida N, Valsecchi V, Pignataro G, Vinciguerra A, Pannaccione A, et al. NCX1 is a new rest target gene: role in cerebral ischemia. Neurobiol Dis. 2013;50:76–85.

    Article  CAS  PubMed  Google Scholar 

  74. Luo J, Wang Y, Chen X, Chen H, Kintner DB, Shull GE, et al. Increased tolerance to ischemic neuronal damage by knockdown of Na+–Ca2+ exchanger isoform 1. Ann N Y Acad Sci. 2007;1099:292–305.

    Article  CAS  PubMed  Google Scholar 

  75. Formisano L, Saggese M, Secondo A, Sirabella R, Vito P, Valsecchi V, et al. The two isoforms of the Na+/Ca2+ exchanger, NCX1 and NCX3, constitute novel additional targets for the prosurvival action of Akt/protein kinase B pathway. Mol Pharmacol. 2008;73:727–37.

    Article  CAS  PubMed  Google Scholar 

  76. Pignataro G, Cuomo O, Esposito E, Sirabella R, Di Renzo G, Annunziato L. ASIC1a contributes to neuroprotection elicited by ischemic preconditioning and postconditioning. Int J Physiol Pathophysiol Pharmacol. 2011;3:1–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Pignataro G, Boscia F, Esposito E, Sirabella R, Cuomo O, Vinciguerra A, et al. NCX1 and NCX3: two new effectors of delayed preconditioning in brain ischemia. Neurobiol Dis. 2012;45:616–23.

    Article  CAS  PubMed  Google Scholar 

  78. Pignataro G, Cuomo O, Vinciguerra A, Sirabella R, Esposito E, Boscia F, et al. NCX as a key player in the neuroprotection exerted by ischemic preconditioning and postconditioning. Adv Exp Med Biol. 2013;961:223–40.

    Article  CAS  PubMed  Google Scholar 

  79. Pignataro G, Esposito E, Cuomo O, Sirabella R, Boscia F, Guida N, et al. The NCX3 isoform of the Na+/Ca2+ exchanger contributes to neuroprotection elicited by ischemic postconditioning. J Cereb Blood Flow Metab. 2011;31:362–70.

    Article  CAS  PubMed  Google Scholar 

  80. Valsecchi V, Pignataro G, Del Prete A, Sirabella R, Matrone C, Boscia F, et al. NCX1 is a novel target gene for hypoxia-inducible factor-1 in ischemic brain preconditioning. Stroke. 2011;42:754–63.

    Article  CAS  PubMed  Google Scholar 

  81. Valsecchi V, Pignataro G, Sirabella R, Matrone C, Boscia F, Scorziello A, et al. Transcriptional regulation of ncx1 gene in the brain. Adv Exp Med Biol. 2013;961:137–45.

    Article  CAS  PubMed  Google Scholar 

  82. Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003;26:248–54.

    Article  CAS  PubMed  Google Scholar 

  83. Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci. 2006;7:437–48.

    Article  CAS  PubMed  Google Scholar 

  84. Kirino T. Ischemic tolerance. J Cereb Blood Flow Metab. 2002;22:1283–96.

    Article  PubMed  Google Scholar 

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Acknowledgments

The present study was supported by grants from COFIN 2008, Ricerca Ordinaria 2009, Fondi 5 per mille ANNO 2010 to SDN.

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  1. Division Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, “Federico II” University of Naples, Via Pansini, 5, 80131, Naples, Italy

    Giuseppe Pignataro, Gianfranco Di Renzo & Lucio Annunziato

  2. IRCCS SDN, Via Gianturco, Naples, Italy

    Rossana Sirabella, Serenella Anzilotti & Lucio Annunziato

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  1. Giuseppe Pignataro
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  2. Rossana Sirabella
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Correspondence to Lucio Annunziato.

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Pignataro, G., Sirabella, R., Anzilotti, S. et al. Does Na+/Ca2+ Exchanger, NCX, Represent a New Druggable Target in Stroke Intervention?. Transl. Stroke Res. 5, 145–155 (2014). https://doi.org/10.1007/s12975-013-0308-8

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