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Basis of Ionic Dysregulation in Cerebral Ischemia

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Book cover New Strategies in Stroke Intervention

Part of the book series: Contemporary Neuroscience ((CNEURO))

Abstract

Stroke causes 9% of all deaths around the world and is the second most common cause of death after ischemic heart disease. Enhancing recovery from stroke and limiting ischemic damage are major goals to decrease stroke morbidity and mortality . Brain tissue is extremely sensitive to oxygen and glucose deprivation, and even brief ischemia can initiate a complex sequence of events that ultimately culminates in cellular death. Studies performed during the past 30 years have identified several key pathophysiological events that lead to ischemic neuronal degeneration. The pathophysiological processes in stroke are complex and involve disruption of the blood–brain barrier (BBB), energy failure, loss of cell ion homeostasis, acidosis, increased intracellular calcium levels, excitotoxicity, free radical-mediated toxicity, generation of arachidonic acid products, cytokine-mediated apoptosis, activation of glial cells, and infiltration of leukocytes . In focal cerebral ischemia, ischemic tissue is divided into an infarction core and penumbra. The core is the area of the brain where blood flow is reduced below 10–20% of its normal levels . In the core, rapid anoxic depolarization causes immediate loss of membrane potential followed by the loss of membrane integrity and rapid necrotic cell death. The penumbra is the tissue surrounding the core where the blood flow is partly preserved due to collateral circulation and diffusion .

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References

  1. Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, and Nicotera P. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15: 961–973, 1995.

    Article  PubMed  CAS  Google Scholar 

  2. Annunziato L, Pannaccione A, Cataldi M, Secondo A, Castaldo P, Di Renzo G, and Taglialatela M. Modulation of ion channels by reactive oxygen and nitrogen species: a pathophysiological role in brain aging? Neurobiol Aging 23: 819–834, 2002.

    Article  PubMed  CAS  Google Scholar 

  3. Annunziato L, Pignataro G, Boscia F, Sirabella R, Formisano L, Saggese M, Cuomo O, Gala R, Secondo A, Viggiano D, Molinaro P, Valsecchi V, Tortiglione A, Adornetto A, Scorziello A, Cataldi M, and Di Renzo GF. ncx1, ncx2, and ncx3 gene product expression and function in neuronal anoxia and brain ischemia. Ann N Y Acad Sci 1099: 413–426, 2007.

    Article  PubMed  CAS  Google Scholar 

  4. Aperia A. New roles for an old enzyme: Na,K-ATPase emerges as an interesting drug target. J Intern Med 261: 44–52, 2007.

    Article  PubMed  CAS  Google Scholar 

  5. Arumugam TV, Granger DN, and Mattson MP. Stroke and T-cells. Neuromolecular Med 7: 229–242, 2005.

    Article  PubMed  CAS  Google Scholar 

  6. Arumugam TV, Selvaraj PK, Woodruff TM, and Mattson MP. Targeting ischemic brain injury with intravenous immunoglobulin. Expert Opin Ther Targets 12: 19–29, 2008.

    Article  PubMed  CAS  Google Scholar 

  7. Banasiak KJ, Burenkova O, and Haddad GG. Activation of voltage-sensitive sodium channels during oxygen deprivation leads to apoptotic neuronal death. Neuroscience 126: 31–44, 2004.

    Article  PubMed  CAS  Google Scholar 

  8. Buckler KJ and Honoré E. The lipid-activated two-pore domain K+ channel TREK-1 is resistant to hypoxia: implication for ischaemic neuroprotection. J Physiol 562: 213–222, 2005.

    Article  PubMed  CAS  Google Scholar 

  9. Chamberlin NL and Dingledine R. GABAergic inhibition and the induction of spontaneous epileptiform activity by low chloride and high potassium in the hippocampal slice. Brain Res 445: 12–18, 1988.

    Article  PubMed  CAS  Google Scholar 

  10. Chan SL and Mattson MP. Caspase and calpain substrates: roles in synaptic plasticity and cell death. J Neurosci Res 58: 167–190, 1999.

    Article  PubMed  CAS  Google Scholar 

  11. Chen H and Sun D. The role of Na-K-Cl co-transporter in cerebral ischemia. Neurol Res 27: 280–286, 2005.

    Article  PubMed  CAS  Google Scholar 

  12. Culmsee C and Mattson MP. p53 in neuronal apoptosis. Biochem Biophys Res Commun 331: 761–777, 2005.

    Article  PubMed  CAS  Google Scholar 

  13. Culmsee C, Zhu Y, Krieglstein J, and Mattson MP. Evidence for the involvement of Par-4 in ischemic neuron cell death. J Cereb Blood Flow Metab 21: 334–343, 2001.

    Article  PubMed  CAS  Google Scholar 

  14. Cuomo O, Gala R, Pignataro G, Boscia F, Secondo A, Scorziello A, Pannaccione A, Viggiano D, Adornetto A, Molinaro P, Li XF, Lytton J, Di Renzo G, and Annunziato L. A critical role for the potassium-dependent sodium-calcium exchanger NCKX2 in protection against focal ischemic brain damage. J Neurosci 28: 2053–2063, 2008.

    Article  PubMed  CAS  Google Scholar 

  15. Donnan GA, Fisher M, Macleod M, and Davis SM. Stroke. Lancet 371: 1612–1623, 2008.

    Article  PubMed  CAS  Google Scholar 

  16. Harata N, Wu J, Ishibashi H, Ono K, and Akaike N. Run-down of the GABAA response under experimental ischaemia in acutely dissociated CA1 pyramidal neurones of the rat. J Physiol 500 (Pt 3): 673–688, 1997.

    PubMed  CAS  Google Scholar 

  17. Hartmann J and Konnerth A. Determinants of postsynaptic Ca2+ signaling in Purkinje neurons. Cell Calcium 37: 459–466, 2005.

    Article  PubMed  CAS  Google Scholar 

  18. Inglefield JR and Schwartz-Bloom RD. Activation of excitatory amino acid receptors in the rat hippocampal slice increases intracellular Cl– and cell volume. J Neurochem 71: 1396–1404, 1998.

    Article  PubMed  CAS  Google Scholar 

  19. Jiang C, Agulian S, and Haddad GG. Cl– and Na+ homeostasis during anoxia in rat hypoglossal neurons: intracellular and extracellular in vitro studies. J Physiol 448: 697–708, 1992.

    PubMed  CAS  Google Scholar 

  20. Kiedrowski L. NCX and NCKX operation in ischemic neurons. Ann N Y Acad Sci 1099: 383–395, 2007.

    Article  PubMed  CAS  Google Scholar 

  21. Kitayama J, Kitazono T, Yao H, Ooboshi H, Takaba H, Ago T, Fujishima M, and Ibayashi S. Inhibition of Na+/H+ exchanger reduces infarct volume of focal cerebral ischemia in rats. Brain Res 922: 223–228, 2001.

    Article  PubMed  CAS  Google Scholar 

  22. Kristián T and Siesjö BK. Calcium in ischemic cell death. Stroke 29: 705–718, 1998.

    PubMed  Google Scholar 

  23. Kumar V, Naik RS, Hillert M, and Klein J. Effects of chloride flux modulators in an in vitro model of brain edema formation. Brain Res 1122: 222–229, 2006.

    Article  PubMed  CAS  Google Scholar 

  24. Kwak S and Weiss JH. Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. Curr Opin Neurobiol 16: 281–287, 2006.

    Article  PubMed  CAS  Google Scholar 

  25. Lang F. Mechanisms and significance of cell volume regulation. J Am Coll Nutr 26: 613S–623S, 2007.

    PubMed  CAS  Google Scholar 

  26. Lang F, Föller M, Lang KS, Lang PA, Ritter M, Gulbins E, Vereninov A, and Huber SM. Ion channels in cell proliferation and apoptotic cell death. J Membr Biol 205: 147–157, 2005.

    Article  PubMed  CAS  Google Scholar 

  27. Leis JA, Bekar LK, and Walz W. Potassium homeostasis in the ischemic brain. Glia 50: 407–416, 2005.

    Article  PubMed  Google Scholar 

  28. Leist M, Volbracht C, Kühnle S, Fava E, Ferrando-May E, and Nicotera P. Caspase-mediated apoptosis in neuronal excitotoxicity triggered by nitric oxide. Mol Med 3: 750–764, 1997.

    PubMed  CAS  Google Scholar 

  29. Lenart B, Kintner DB, Shull GE, and Sun D. Na-K-Cl cotransporter-mediated intracellular Na+ accumulation affects Ca2+ signaling in astrocytes in an in vitro ischemic model. J Neurosci 24: 9585–9597, 2004.

    Article  PubMed  CAS  Google Scholar 

  30. Lipski J, Park TI, Li D, Lee SC, Trevarton AJ, Chung KK, Freestone PS, and Bai JZ. Involvement of TRP-like channels in the acute ischemic response of hippocampal CA1 neurons in brain slices. Brain Res 1077: 187–199, 2006.

    Article  PubMed  CAS  Google Scholar 

  31. Liu D, Slevin JR, Lu C, Chan SL, Hansson M, Elmer E, and Mattson MP. Involvement of mitochondrial K+ release and cellular efflux in ischemic and apoptotic neuronal death. J Neurochem 86: 966–979, 2003.

    Article  PubMed  CAS  Google Scholar 

  32. Love S. Oxidative stress in brain ischemia. Brain Pathol 9: 119–131, 1999.

    Article  PubMed  CAS  Google Scholar 

  33. Luo J, Kintner DB, Shull GE, and Sun D. ERK1/2-p90RSK-mediated phosphoryl tion of Na+/H+ exchanger isoform 1. A role in ischemic neuronal death. J Biol Chem 282: 28274–28284, 2007.

    Article  PubMed  CAS  Google Scholar 

  34. Mattson MP. Neurotransmitters in the regulation of neuronal cytoarchitecture. Brain Res 472: 179–212, 1988.

    PubMed  CAS  Google Scholar 

  35. Mattson MP. Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity. Trends Neurosci 21: 53–57, 1998.

    Article  PubMed  CAS  Google Scholar 

  36. Mattson MP. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Med 3: 65–94, 2003.

    Article  PubMed  CAS  Google Scholar 

  37. Mattson MP. Calcium and neurodegeneration. Aging Cell 6: 337–350, 2007.

    Article  PubMed  CAS  Google Scholar 

  38. Mattson MP, Guthrie PB, and Kater SB. A role for Na+-dependent Ca2+ extrusion in protection against neuronal excitotoxicity. FASEB J 3: 2519–2526, 1989.

    PubMed  CAS  Google Scholar 

  39. Mattson MP, Culmsee C, and Yu ZF. Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res 301: 173–187, 2000.

    Article  PubMed  CAS  Google Scholar 

  40. Mattson MP, Rychlik B, Chu C, and Christakos S. Evidence for calcium-reducing and excito-protective roles for the calcium-binding protein calbindin-D28k in cultured hippocampal neurons. Neuron 6: 41–51, 1991.

    Article  PubMed  CAS  Google Scholar 

  41. Mittmann T, Qü M, Zilles K, and Luhmann HJ. Long-term cellular dysfunction after focal cerebral ischemia: in vitro analyses. Neuroscience 85: 15–27, 1998.

    Article  PubMed  CAS  Google Scholar 

  42. Mongin AA. Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm. Pathophysiology 14: 183–193, 2007.

    Article  PubMed  CAS  Google Scholar 

  43. Nakamichi N, Oikawa H, Kambe Y, and Yoneda Y. Relevant modulation by ferrous ions of N-methyl-D-aspartate receptors in ischemic brain injuries. Curr Neurovasc Res 1: 429–440, 2004.

    Article  PubMed  CAS  Google Scholar 

  44. Okada Y, Maeno E, Shimizu T, Dezaki K, Wang J, and Morishima S. Receptor-mediated control of regulatory volume decrease (RVD) and apoptotic volume decrease (AVD). J Physiol 532: 3–16, 2001.

    Article  PubMed  CAS  Google Scholar 

  45. Okada Y, Shimizu T, Maeno E, Tanabe S, Wang X, and Takahashi N. Volume-sensitive chloride channels involved in apoptotic volume decrease and cell death. J Membr Biol 209: 21–29, 2006.

    Article  PubMed  CAS  Google Scholar 

  46. Payne JA. Functional characterization of the neuronal-specific K-Cl cotransporter: implications for [K+]o regulation. Am J Physiol 273: C1516–C1525, 1997.

    PubMed  CAS  Google Scholar 

  47. Pedersen SF, O'Donnell ME, Anderson SE, and Cala PM. Physiology and pathophysiology of Na+/H+ exchange and Na+-K+-2Cl– cotransport in the heart, brain, and blood. Am J Physiol Regul Integr Comp Physiol 291: R1–R25, 2006.

    PubMed  CAS  Google Scholar 

  48. Pinheiro PS and Mulle C. Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat Rev Neurosci 9: 423–436, 2008.

    Article  PubMed  CAS  Google Scholar 

  49. Rosenberg GA. Ischemic brain edema. Prog Cardiovasc Dis 42: 209–216, 1999.

    Article  PubMed  CAS  Google Scholar 

  50. Sah R and Schwartz-Bloom RD. Optical imaging reveals elevated intracellular chloride in hippocampal pyramidal neurons after oxidative stress. J Neurosci 19: 9209–9217, 1999.

    PubMed  CAS  Google Scholar 

  51. Schwartz-Bloom RD and Sah R. Gamma-aminobutyric acid(A) neurotransmission and cerebral ischemia. J Neurochem 77: 353–371, 2001.

    Article  PubMed  CAS  Google Scholar 

  52. Simard JM, Tarasov KV, and Gerzanich V. Non-selective cation channels, transient receptor potential channels and ischemic stroke. Biochim Biophys Acta 1772: 947–957, 2007.

    PubMed  CAS  Google Scholar 

  53. Takahashi A, Camacho P, Lechleiter JD, and Herman B. Measurement of intracellular calcium. Physiol Rev 79: 1089–1125, 1999.

    PubMed  CAS  Google Scholar 

  54. Wei L, Yu SP, Gottron F, Snider BJ, Zipfel GJ, and Choi DW. Potassium channel blockers attenuate hypoxia- and ischemia-induced neuronal death in vitro and in vivo. Stroke 34: 1281–1286, 2003.

    Article  PubMed  CAS  Google Scholar 

  55. Weinstein PR, Hong S, and Sharp FR. Molecular identification of the ischemic penumbra. Stroke 35: 2666–2670, 2004.

    Article  PubMed  CAS  Google Scholar 

  56. Werth JL and Thayer SA. Mitochondria buffer physiological calcium loads in cultured rat dorsal root ganglion neurons. J Neurosci 14: 348–356, 1994.

    PubMed  CAS  Google Scholar 

  57. Won SJ, Kim DY, and Gwag BJ. Cellular and molecular pathways of ischemic neuronal death. J Biochem Mol Biol 35: 67–86, 2002.

    PubMed  CAS  Google Scholar 

  58. Xiong ZG, Chu XP, and Simon RP. Ca2+-permeable acid-sensing ion channels and ischemic brain injury. J Membr Biol 209: 59–68, 2006.

    Article  PubMed  CAS  Google Scholar 

  59. Yu SP. Regulation and critical role of potassium homeostasis in apoptosis. Prog Neurobiol 70: 363–386, 2003.

    Article  PubMed  CAS  Google Scholar 

  60. Yu SP, Yeh C, Strasser U, Tian M, and Choi DW. NMDA receptor-mediated K+ efflux and neuronal apoptosis. Science 284: 336–339, 1999.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. School of Biomedical Sciences, The University of Queensland, 4072, Brisbane, QLD, Australia

    Thiruma V Arumugam

  2. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 21224, Baltimore, MD, USA

    Eitan Okun & Mark P Mattson

Authors
  1. Thiruma V Arumugam
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  2. Eitan Okun
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  3. Mark P Mattson
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Corresponding author

Correspondence to Thiruma V Arumugam .

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Editors and Affiliations

  1. Fac. Medicina e Chirurgia, Università di Napoli, Via Sergio Pansini 5, Napoli, 80131, Italy

    Lucio Annunziato

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Arumugam, T.V., Okun, E., Mattson, M.P. (2009). Basis of Ionic Dysregulation in Cerebral Ischemia. In: Annunziato, L. (eds) New Strategies in Stroke Intervention. Contemporary Neuroscience. Humana Press. https://doi.org/10.1007/978-1-60761-280-3_1

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