Na+/H+ Exchangers as Therapeutic Targets for Cerebral Ischemia

Part of the Springer Series in Translational Stroke Research book series (SSTSR)


The Na+/H+ exchangers (NHE) are a family of membrane transporters that catalyzes the exchange of intracellular H+ with extracellular Na+ and plays a role in regulating intracellular pH and cell volume. Following cerebral ischemia, the “housekeeping” NHE isoform 1 (NHE-1) is stimulated by intracellular acidosis to remove excess H+. Overstimulation of NHE-1 causes accumulation of Na+ and Ca2+ inside the cell through the reversal mode of Na+/Ca2+ exchange (NCX) and eventually contributes to cell death. Pharmacological inhibition or genetic knockdown of NHE-1 is neuroprotective in both in vitro and in vivo ischemia models as shown by reduced neuronal death and blockade of intracellular Ca2+ and Na+ accumulation. Inhibition of NHE-1 not only reduces brain infarct volume but also improves long-term neurological functions. Inhibition of NHE-1 also has a profound effect on neuroinflammation and edema formation, providing a longer treatment time window for stroke therapy. Therefore, NHE-1 merges as an important target for developing new therapeutics for stroke treatment.


Cerebral Ischemia Middle Cerebral Artery Occlusion Intracellular Acidosis Mouse Middle Cerebral Artery Occlusion Mouse Middle Cerebral Artery Occlusion Model 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by NIH grants R01NS 48216 and R01NS 38118 (D. Sun).


  1. 1.
    An J, Varadarajan SG, Camara A, Chen Q, Novalija E, Gross GJ, Stowe DF. Blocking Na(+)/H(+) exchange reduces [Na(+)](i) and [Ca(2+)](i) load after ischemia and improves function in intact hearts. Am J Physiol Heart Circ Physiol. 2001;281:H2398–409.PubMedGoogle Scholar
  2. 2.
    Ayata C, Ropper AH. Ischaemic brain oedema. J Clin Neurosci. 2002;9:113–24.PubMedCrossRefGoogle Scholar
  3. 3.
    Back SA, Luo NL, Borenstein NS, Levine JM, Volpe JJ, Kinney HC. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci. 2001;21:1302–12.PubMedGoogle Scholar
  4. 4.
    Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87(1):245–313.PubMedCrossRefGoogle Scholar
  5. 5.
    Besse S, Tanguy S, Boucher F, Huraux C, Riou B, Swynghedauw B, de Leiris J. Protection of endothelial-derived vasorelaxation with cariporide, a sodium-proton exchanger inhibitor, after prolonged hypoxia and hypoxia-reoxygenation: effect of age. Eur J Pharmacol. 2006;531:187–93.PubMedCrossRefGoogle Scholar
  6. 6.
    Biemesderfer D, Reilly RF, Exner M, Igarashi P, Aronson PS. Immunocytochemical characterization of Na(+)-H+ exchanger isoform NHE-1 in rabbit kidney. Am J Physiol. 1992;263:F833–40.PubMedGoogle Scholar
  7. 7.
    Brett CL, Wei Y, Donowitz M, Rao R. Human Na+/H+ exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria. Am J Physiol Cell Physiol. 2002;282:C1031–41.PubMedGoogle Scholar
  8. 8.
    Brown RC, Davis TP. Calcium modulation of adherens and tight junction function: a potential mechanism for blood-brain barrier disruption after stroke. Stroke. 2002;33:1706–11.PubMedCrossRefGoogle Scholar
  9. 9.
    Cengiz P, Kleman N, Uluc K, Kendigelen P, Hagemann T, Akture E, Messing A, Ferrazzano P, Sun D. Inhibition of Na+/H+ exchanger isoform 1 is neuroprotective in neonatal hypoxic ischemic brain injury. Antioxid Redox Signal. 2011;14:1803–13.PubMedCrossRefGoogle Scholar
  10. 10.
    Chu CT, Levinthal DJ, Kulich SM, Chalovich EM, DeFranco DB. Oxidative neuronal injury. The dark side of ERK1/2. Eur J Biochem. 2004;271:2060–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Daskalopoulos R, Korcok J, Farhangkhgoee P, Karmazyn M, Gelb AW, Wilson JX. Propofol protection of sodium-hydrogen exchange activity sustains glutamate uptake during oxidative stress. Anesth Analg. 2001;93:1199–204.PubMedCrossRefGoogle Scholar
  12. 12.
    De Vito P. The sodium/hydrogen exchanger: a possible mediator of immunity. Cell Immunol. 2006;240:69–85.PubMedCrossRefGoogle Scholar
  13. 13.
    Denker SP, Barber DL. Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J Cell Biol. 2002;159(6):1087–96.PubMedCrossRefGoogle Scholar
  14. 14.
    Denker SP, Huang DC, Orlowski J, Furthmayr H, Barber DL. Direct binding of the Na–H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H+ translocation. Mol Cell. 2000;6:1425–36.PubMedCrossRefGoogle Scholar
  15. 15.
    Fagan SC, Hess DC, Hohnadel EJ, Pollock DM, Ergul A. Targets for vascular protection after acute ischemic stroke. Stroke. 2004;35:2220–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Ferriero DM. Neonatal brain injury. N Engl J Med. 2004;351:1985–95.PubMedCrossRefGoogle Scholar
  17. 17.
    Fliegel L. The Na+/H+ exchanger isoform 1. Int J Biochem Cell Biol. 2005;37:33–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Graeber MB, Streit WJ. Microglia: biology and pathology. Acta Neuropathol. 2010;119(1):89–105.PubMedCrossRefGoogle Scholar
  19. 19.
    Grinstein S, Woodside M, Waddell TK, Downey GP, Orlowski J, Pouyssegur J, Wong DC, Foskett JK. Focal localization of the NHE-1 isoform of the Na+/H+ antiport: assessment of effects on intracellular pH. EMBO J. 1993;12:5209–18.PubMedGoogle Scholar
  20. 20.
    Harhaj NS, Antonetti DA. Regulation of tight junctions and loss of barrier function in pathophysiology. Int J Biochem Cell Biol. 2004;36:1206–37.PubMedCrossRefGoogle Scholar
  21. 21.
    Harrigan TJ, Abdullaev IF, Jourd’heuil D, Mongin AA. Activation of microglia with zymosan promotes excitatory amino acid release via volume-regulated anion channels: the role of NADPH oxidases. J Neurochem. 2008;106:2449–62.PubMedCrossRefGoogle Scholar
  22. 22.
    Henderson LM, Chappell JB, Jones OT. Internal pH changes associated with the activity of NADPH oxidase of human neutrophils. Further evidence for the presence of an H+ conducting channel. Biochem J. 1988;251:563–7.PubMedGoogle Scholar
  23. 23.
    Hsu CY, Ahmed SH, Lees KR. The therapeutic time window—theoretical and practical considerations. J Stroke Cerebrovasc Dis. 2000;9(6 Pt 2):24–31.PubMedCrossRefGoogle Scholar
  24. 24.
    Huber JD, Egleton RD, Davis TP. Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci. 2001;24:719–25.PubMedCrossRefGoogle Scholar
  25. 25.
    Hwang IK, Yoo KY, An SJ, Li H, Lee CH, Choi JH, Lee JY, Lee BH, Kim YM, Kwon YG, Won MH. Late expression of Na+/H+ exchanger 1 (NHE1) and neuroprotective effects of NHE inhibitor in the gerbil hippocampal CA1 region induced by transient ischemia. Exp Neurol. 2008;212:314–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Jakubovicz DE, Klip A. Lactic acid-induced swelling in C6 glial cells via Na+/H+ exchange. Brain Res. 1989;485:215–24.PubMedCrossRefGoogle Scholar
  27. 27.
    Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol. 2010;87(5):779–89.PubMedCrossRefGoogle Scholar
  28. 28.
    Jovanovic JN, Sihra TS, Nairn AC, Hemmings Jr HC, Greengard P, Czernik AJ. Opposing changes in phosphorylation of specific sites in synapsin I during Ca2+-dependent glutamate release in isolated nerve terminals. J Neurosci. 2001;21:7944–53.PubMedGoogle Scholar
  29. 29.
    Kendall GS, Robertson NJ, Iwata O, Peebles D, Raivich G. N-methyl-isobutyl-amiloride ameliorates brain injury when commenced before hypoxia ischemia in neonatal mice. Pediatr Res. 2006;59:227–31.PubMedCrossRefGoogle Scholar
  30. 30.
    Khaled AR, Moor AN, Li A, Kim K, Ferris DK, Muegge K, Fisher RJ, Fliegel L, Durum SK. Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization. Mol Cell Biol. 2001;21:7545–57.PubMedCrossRefGoogle Scholar
  31. 31.
    Kintner DB, Su G, Lenart B, Ballard AJ, Meyer JW, Ng LL, Shull GE, Sun D. Increased tolerance to oxygen and glucose deprivation in astrocytes from Na+/H+ exchanger isoform 1 null mice. Am J Physiol Cell Physiol. 2004;287:C12–21.PubMedCrossRefGoogle Scholar
  32. 32.
    Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Kuribayashi Y, Itoh N, Kitano M, Ohashi N. Cerebroprotective properties of SM-20220, a potent Na+/H+ exchange inhibitor, in transient cerebral ischemia in rats. Eur J Pharmacol. 1999;383:163–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci. 2007;27(10):2596–605.PubMedCrossRefGoogle Scholar
  35. 35.
    Lam TI, Wise PM, O’Donnell ME. Cerebral microvascular endothelial cell Na/H exchange: evidence for the presence of NHE1 and NHE2 isoforms and regulation by arginine vasopressin. Am J Physiol Cell Physiol. 2009;297:C278–89.PubMedCrossRefGoogle Scholar
  36. 36.
    Lee BK, Lee DH, Park S, Park SL, Yoon JS, Lee MG, Lee S, Yi KY, Yoo SE, Lee KH, Kim YS, Lee SH, Baik EJ, Moon CH, Jung YS. Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on glutamate-induced neuronal cell death and ischemia-induced cerebral infarct. Brain Res. 2009;1248:22–30.PubMedCrossRefGoogle Scholar
  37. 37.
    Liu Y, Kintner DB, Chanana V, Algharabli J, Chen X, Gao Y, Chen J, Ferrazzano P, Olson JK, Sun D. Activation of microglia depends on Na+/H+ exchange-mediated H+ homeostasis. J Neurosci. 2010;30:15210–20.PubMedCrossRefGoogle Scholar
  38. 38.
    Luo J, Chen H, Kintner DB, Shull GE, Sun D. Decreased neuronal death in Na+/H+ exchanger isoform 1-null mice after in vitro and in vivo ischemia. J Neurosci. 2005;25:11256–68.PubMedCrossRefGoogle Scholar
  39. 39.
    Luo J, Kintner DB, Shull GE, Sun D. ERK1/2-p90RSK-mediated phosphorylation of Na(+)/H(+) exchanger isoform 1. A role in ischemic neuronal death. J Biol Chem. 2007;282:28274–84.PubMedCrossRefGoogle Scholar
  40. 40.
    Luo J, Sun D. Physiology and pathophysiology of Na(+)/H(+) exchange isoform 1 in the central nervous system. Curr Neurovasc Res. 2007;4:205–15.PubMedCrossRefGoogle Scholar
  41. 41.
    Manhas N, Shi Y, Taunton J, Sun D. p90 activation contributes to cerebral ischemic damage via phosphorylation of Na+/H+ exchanger isoform 1. J Neurochem. 2010;114:1476–86.PubMedGoogle Scholar
  42. 42.
    Masereel B, Pochet L, Laeckmann D. An overview of inhibitors of Na(+)/H(+) exchanger. Eur J Med Chem. 2003;38:547–54.PubMedCrossRefGoogle Scholar
  43. 43.
    Matsumoto Y, Yamamoto S, Suzuki Y, Tsuboi T, Terakawa S, Ohashi N, Umemura K. Na+/H+ exchanger inhibitor, SM-20220, is protective against excitotoxicity in cultured cortical neurons. Stroke. 2004;35:185–90.PubMedCrossRefGoogle Scholar
  44. 44.
    Mentzer Jr RM, Bartels C, Bolli R, Boyce S, Buckberg GD, Chaitman B, Haverich A, Knight J, Menasche P, Myers ML, Nicolau J, Simoons M, Thulin L, Weisel RD. Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study. Ann Thorac Surg. 2008;85:1261–70.PubMedCrossRefGoogle Scholar
  45. 45.
    Moor AN, Gan XT, Karmazyn M, Fliegel L. Activation of Na+/H+ exchanger-directed protein kinases in the ischemic and ischemic-reperfused rat myocardium. J Biol Chem. 2001;276:16113–22.PubMedCrossRefGoogle Scholar
  46. 46.
    Namura S, Iihara K, Takami S, Nagata I, Kikuchi H, Matsushita K, Moskowitz MA, Bonventre JV, Alessandrini A. Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia. Proc Natl Acad Sci U S A. 2001;98:11569–74.PubMedCrossRefGoogle Scholar
  47. 47.
    Numata M, Orlowski J. Molecular cloning and characterization of a novel (Na+, K+)/H+ exchanger localized to the trans-Golgi network. J Biol Chem. 2001;276:17387–94.PubMedCrossRefGoogle Scholar
  48. 48.
    Orlowski J, Grinstein S. Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflugers Arch. 2004;447:549–65.PubMedCrossRefGoogle Scholar
  49. 49.
    Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S. Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci U S A. 2002;99:1259–63.PubMedCrossRefGoogle Scholar
  50. 50.
    Park SL, Lee DH, Yoo SE, Jung YS. The effect of Na(+)/H(+) exchanger-1 inhibition by sabiporide on blood-brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro. Brain Res. 2010;1366:189–96.PubMedCrossRefGoogle Scholar
  51. 51.
    Petito CK, Babiak T. Early proliferative changes in astrocytes in postischemic noninfarcted rat brain. Ann Neurol. 1982;11:510–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Petrecca K, Atanasiu R, Grinstein S, Orlowski J, Shrier A. Subcellular localization of the Na+/H+ exchanger NHE1 in rat myocardium. Am J Physiol. 1999;276:H709–17.PubMedGoogle Scholar
  53. 53.
    Plesnila N, Haberstok J, Peters J, Kolbl I, Baethmann A, Staub F. Effect of lactacidosis on cell volume and intracellular pH of astrocytes. J Neurotrauma. 1999;16:831–41.PubMedCrossRefGoogle Scholar
  54. 54.
    Putney LK, Denker SP, Barber DL. The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions. Annu Rev Pharmacol Toxicol. 2002;42:527–52.PubMedCrossRefGoogle Scholar
  55. 55.
    Robertson NJ, Cowan FM, Cox IJ, Edwards AD. Brain alkaline intracellular pH after neonatal encephalopathy. Ann Neurol. 2002;52:732–42.PubMedCrossRefGoogle Scholar
  56. 56.
    Rotin D, Grinstein S. Impaired cell volume regulation in Na(+)-H+ exchange-deficient mutants. Am J Physiol. 1989;257:C1158–65.PubMedGoogle Scholar
  57. 57.
    Shi Y, Chanana V, Watters JJ, Ferrazzano P, Sun D. Role of sodium/hydrogen exchanger isoform 1 in microglial activation and proinflammatory responses in ischemic brains. J Neurochem. 2011;119(1):124–35.PubMedCrossRefGoogle Scholar
  58. 58.
    Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35.PubMedCrossRefGoogle Scholar
  59. 59.
    Suzuki Y, Matsumoto Y, Ikeda Y, Kondo K, Ohashi N, Umemura K. SM-20220, a Na(+)/H(+) exchanger inhibitor: effects on ischemic brain damage through edema and neutrophil accumulation in a rat middle cerebral artery occlusion model. Brain Res. 2002;945:242–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Takahashi KI, Copenhagen DR. Modulation of neuronal function by intracellular pH. Neurosci Res. 1996;24:109–16.PubMedCrossRefGoogle Scholar
  61. 61.
    Tambuyzer BR, Ponsaerts P, Nouwen EJ. Microglia: gatekeepers of central nervous system immunology. J Leukoc Biol. 2009;85:352–70.PubMedCrossRefGoogle Scholar
  62. 62.
    Wang Y, Luo J, Chen X, Chen H, Cramer SW, Sun D. Gene inactivation of Na+/H+ exchanger isoform 1 attenuates apoptosis and mitochondrial damage following transient focal cerebral ischemia. Eur J Neurosci. 2008;28:51–61.PubMedCrossRefGoogle Scholar
  63. 63.
    Yao H, Haddad GG. Calcium and pH homeostasis in neurons during hypoxia and ischemia. Cell Calcium. 2004;36:247–55.PubMedCrossRefGoogle Scholar
  64. 64.
    Yao H, Ma E, Gu XQ, Haddad GG. Intracellular pH regulation of CA1 neurons in Na(+)/H(+) isoform 1 mutant mice. J Clin Invest. 1999;104:637–45.PubMedCrossRefGoogle Scholar
  65. 65.
    Yenari MA, Kauppinen TM, Swanson RA. Microglial activation in stroke: therapeutic targets. Neurotherapeutics. 2010;7(4):378–91.PubMedCrossRefGoogle Scholar
  66. 66.
    Yoshioka H, Niizuma K, Katsu M, Okami N, Sakata H, Kim GS, Narasimhan P, Chan PH. NADPH oxidase mediates striatal neuronal injury after transient global cerebral ischemia. J Cereb Blood Flow Metab. 2010;31(3):868–80.PubMedCrossRefGoogle Scholar
  67. 67.
    Zachos NC, Tse M, Donowitz M. Molecular physiology of intestinal Na+/H+ exchange. Annu Rev Physiol. 2005;67:411–43.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Neuroscience Training ProgramUniversity of WisconsinMadisonUSA
  2. 2.Department of NeurologyUniversity of PittsburghPittsburghUSA
  3. 3.Department of Neurological SurgeryUniversity of WisconsinMadisonUSA

Personalised recommendations