Molecular Neurobiology

, Volume 41, Issue 2–3, pp 172–179 | Cite as

Reperfusion and Neurovascular Dysfunction in Stroke: from Basic Mechanisms to Potential Strategies for Neuroprotection

  • Joo Eun Jung
  • Gab Seok Kim
  • Hai Chen
  • Carolina M. Maier
  • Purnima Narasimhan
  • Yun Seon Song
  • Kuniyasu Niizuma
  • Masataka Katsu
  • Nobuya Okami
  • Hideyuki Yoshioka
  • Hiroyuki Sakata
  • Christina E. Goeders
  • Pak H. Chan
Article

Abstract

Effective stroke therapies require recanalization of occluded cerebral blood vessels. However, reperfusion can cause neurovascular injury, leading to cerebral edema, brain hemorrhage, and neuronal death by apoptosis/necrosis. These complications, which result from excess production of reactive oxygen species in mitochondria, significantly limit the benefits of stroke therapies. We have developed a focal stroke model using mice deficient in mitochondrial manganese-superoxide dismutase (SOD2−/+) to investigate neurovascular endothelial damage that occurs during reperfusion. Following focal stroke and reperfusion, SOD2−/+ mice had delayed blood-brain barrier breakdown, associated with activation of matrix metalloproteinase and high brain hemorrhage rates, whereas a decrease in apoptosis and hemorrhage was observed in SOD2 overexpressors. Thus, induction and activation of SOD2 is a novel strategy for neurovascular protection after ischemia/reperfusion. Our recent study identified the signal transducer and activator of transcription 3 (STAT3) as a transcription factor of the mouse SOD2 gene. During reperfusion, activation of STAT3 and its recruitment into the SOD2 gene were blocked, resulting in increased oxidative stress and neuronal apoptosis. In contrast, pharmacological activation of STAT3 induced SOD2 expression, which limits ischemic neuronal death. Our studies point to antioxidant-based neurovascular protective strategies as potential treatments to expand the therapeutic window of currently approved therapies.

Keywords

Cerebral ischemia Oxidative stress Reactive oxygen species Mitochondria Mn-SOD STAT3 NADPH oxidase CK2 Neuroprotective signaling 

Notes

Acknowledgments

This work was supported by grants P50 NS014543, RO1 NS025372, RO1 NS036147, and RO1 NS038653 from the National Institutes of Health and by the James R. Doty Endowment. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

References

  1. 1.
    Saito A, Maier CM, Narasimhan P, Nishi T, Song YS, Yu F, Liu J, Lee Y-S, Nito C, Kamada H, Dodd RL, Hsieh LB, Hassid B, Kim EE, González M, Chan PH (2005) Oxidative stress and neuronal death/survival signaling in cerebral ischemia. Mol Neurobiol 31:105–116CrossRefPubMedGoogle Scholar
  2. 2.
    Sugawara T, Chan PH (2003) Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal 5:597–607CrossRefPubMedGoogle Scholar
  3. 3.
    Chan PH (1996) Role of oxidants in ischemic brain damage. Stroke 27:1124–1129PubMedGoogle Scholar
  4. 4.
    Li Y, Huang T-T, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ (1995) Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 11:376–381CrossRefPubMedGoogle Scholar
  5. 5.
    Kim GW, Kondo T, Noshita N, Chan PH (2002) Manganese superoxide dismutase deficiency exacerbates cerebral infarction after focal cerebral ischemia/reperfusion in mice. Implications for the production and role of superoxide radicals. Stroke 33:809–815CrossRefPubMedGoogle Scholar
  6. 6.
    Maier CM, Hsieh L, Crandall T, Narasimhan P, Chan PH (2006) Evaluating therapeutic targets for reperfusion-related brain hemorrhage. Ann Neurol 59:929–938CrossRefPubMedGoogle Scholar
  7. 7.
    Jung JE, Kim GS, Narasimhan P, Song YS, Chan PH (2009) Regulation of Mn-superoxide dismutase activity and neuroprotection by STAT3 in mice after cerebral ischemia. J Neurosci 29:7003–7014CrossRefPubMedGoogle Scholar
  8. 8.
    Darnell JE Jr (1997) STATs and gene regulation. Science 277:1630–1635CrossRefPubMedGoogle Scholar
  9. 9.
    Levy DE, Lee C-k (2002) What does Stat3 do? J Clin Invest 109:1143–1148PubMedGoogle Scholar
  10. 10.
    Bromberg J, Darnell JE Jr (2000) The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19:2468–2473CrossRefPubMedGoogle Scholar
  11. 11.
    Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134:707–716PubMedGoogle Scholar
  12. 12.
    Fujimura M, Tominaga T, Chan PH (2005) Neuroprotective effect of an antioxidant in ischemic brain injury: involvement of neuronal apoptosis. Neurocrit Care 2:59–66CrossRefPubMedGoogle Scholar
  13. 13.
    Maier CM, Chan PH (2002) Role of superoxide dismutases in oxidative damage and neurodegenerative disorders. Neuroscientist 8:323–334CrossRefPubMedGoogle Scholar
  14. 14.
    Phillis JW (1994) A "radical" view of cerebral ischemic injury. Prog Neurobiol 42:441–448CrossRefPubMedGoogle Scholar
  15. 15.
    MacMillan-Crow LA, Crow JP, Kerby JD, Beckman JS, Thompson JA (1996) Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts. Proc Natl Acad Sci USA 93:11853–11858CrossRefPubMedGoogle Scholar
  16. 16.
    Brorson JR, Schumacker PT, Zhang H (1999) Nitric oxide acutely inhibits neuronal energy production. J Neurosci 19:147–158PubMedGoogle Scholar
  17. 17.
    Imaizumi S, Woolworth V, Fishman RA, Chan PH (1990) Liposome-entrapped superoxide dismutase reduces cerebral infarction in cerebral ischemia in rats. Stroke 21:1312–1317PubMedGoogle Scholar
  18. 18.
    Kinouchi H, Epstein CJ, Mizui T, Carlson E, Chen SF, Chan PH (1991) Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc Natl Acad Sci USA 88:11158–11162CrossRefPubMedGoogle Scholar
  19. 19.
    Uyama O, Matsuyama T, Michishita H, Nakamura H, Sugita M (1992) Protective effects of human recombinant superoxide dismutase on transient ischemic injury of CA1 neurons in gerbils. Stroke 23:75–81PubMedGoogle Scholar
  20. 20.
    Kajita Y, Suzuki Y, Oyama H, Tanazawa T, Takayasu M, Shibuya M, Sugita K (1994) Combined effect of L-arginine and superoxide dismutase on the spastic basilar artery after subarachnoid hemorrhage in dogs. J Neurosurg 80:476–483CrossRefPubMedGoogle Scholar
  21. 21.
    Kamii H, Kato I, Kinouchi H, Chan PH, Epstein CJ, Akabane A, Okamoto H, Yoshimoto T (1999) Amelioration of vasospasm after subarachnoid hemorrhage in transgenic mice overexpressing CuZn–superoxide dismutase. Stroke 30:867–871PubMedGoogle Scholar
  22. 22.
    Miller FJ Jr, Gutterman DD, Rios CD, Heistad DD, Davidson BL (1998) Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis. Circ Res 82:1298–1305PubMedGoogle Scholar
  23. 23.
    Pfister H-W, Koedel U, Lorenzl S, Tomasz A (1992) Antioxidants attenuate microvascular changes in the early phase of experimental pneumococcal meningitis in rats. Stroke 23:1798–1804PubMedGoogle Scholar
  24. 24.
    Chopp M, Chan PH, Hsu CY, Cheung ME, Jacobs TP (1996) DNA damage and repair in central nervous system injury. National Institute of Neurological Disorders and Stroke workshop summary. Stroke 27:363–369PubMedGoogle Scholar
  25. 25.
    Wahlgren NG, Ahmed N (2004) Neuroprotection in cerebral ischaemia: facts and fancies—the need for new approaches. Cerebrovasc Dis 17(suppl 1):153–166CrossRefPubMedGoogle Scholar
  26. 26.
    Brennan AM, Suh SW, Won SJ, Narasimhan P, Kauppinen TM, Lee H, Edling Y, Chan PH, Swanson RA (2009) NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci 12:857–863CrossRefPubMedGoogle Scholar
  27. 27.
    Zelko IN, Mariani TJ, Folz RJ (2002) Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med 33:337–349CrossRefPubMedGoogle Scholar
  28. 28.
    St. Clair D (2004) Manganese superoxide dismutase: genetic variation and regulation. J Nutr 134:3190S–3191SPubMedGoogle Scholar
  29. 29.
    Petersen SV, Enghild JJ (2005) Extracellular superoxide dismutase: structural and functional considerations of a protein shaped by two different disulfide bridge patterns. Biomed Pharmacother 59:175–182CrossRefPubMedGoogle Scholar
  30. 30.
    Murakami K, Kondo T, Kawase M, Li Y, Sato S, Chen SF, Chan PH (1998) Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci 18:205–213PubMedGoogle Scholar
  31. 31.
    Fujimura M, Morita-Fujimura Y, Kawase M, Copin J-C, Calagui B, Epstein CJ, Chan PH (1999) Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome c and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice. J Neurosci 19:3414–3422PubMedGoogle Scholar
  32. 32.
    Keller JN, Kindy MS, Holtsberg FW, St. Clair DK, Yen H-C, Germeyer A, Steiner SM, Bruce-Keller AJ, Hutchins JB, Mattson MP (1998) Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci 18:687–697PubMedGoogle Scholar
  33. 33.
    Wong GHW, Elwell JH, Oberley LW, Goeddel DV (1989) Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor. Cell 58:923–931CrossRefPubMedGoogle Scholar
  34. 34.
    Gonzalez-Zulueta M, Ensz LM, Mukhina G, Lebovitz RM, Zwacka RM, Engelhardt JF, Oberley LW, Dawson VL, Dawson TM (1998) Manganese superoxide dismutase protects nNOS neurons from NMDA and nitric oxide-mediated neurotoxicity. J Neurosci 18:2040–2055PubMedGoogle Scholar
  35. 35.
    Wispé JR, Warner BB, Clark JC, Dey CR, Neuman J, Glasser SW, Crapo JD, Chang L-Y, Whitsett JA (1992) Human Mn-superoxide dismutase in pulmonary epithelial cells of transgenic mice confers protection from oxygen injury. J Biol Chem 267:23937–23941PubMedGoogle Scholar
  36. 36.
    Dougall WC, Nick HS (1991) Manganese superoxide dismutase: a hepatic acute phase protein regulated by interleukin-6 and glucocorticoids. Endocrinology 129:2376–2384CrossRefPubMedGoogle Scholar
  37. 37.
    Wong GHW, Goeddel DV (1988) Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective mechanism. Science 242:941–944CrossRefPubMedGoogle Scholar
  38. 38.
    Visner GA, Dougall WC, Wilson JM, Burr IA, Nick HS (1990) Regulation of manganese superoxide dismutase by lipopolysaccharide, interleukin-1, and tumor necrosis factor. Role in the acute inflammatory response. J Biol Chem 265:2856–2864PubMedGoogle Scholar
  39. 39.
    Valentine JF, Nick HS (1992) Acute-phase induction of manganese superoxide dismutase in intestinal epithelial cell lines. Gastroenterology 103:905–912PubMedGoogle Scholar
  40. 40.
    Akashi M, Hachiya M, Paquette RL, Osawa Y, Shimizu S, Suzuki G (1995) Irradiation increases manganese superoxide dismutase mRNA levels in human fibroblasts. Possible mechanisms for its accumulation. J Biol Chem 270:15864–15869CrossRefPubMedGoogle Scholar
  41. 41.
    Borg LAH, Cagliero E, Sandler S, Welsh N, Eizirik DL (1992) Interleukin-1β increases the activity of superoxide dismutase in rat pancreatic islets. Endocrinology 130:2851–2857CrossRefPubMedGoogle Scholar
  42. 42.
    Whitsett JA, Clark JC, Wispé JR, Pryhuber GS (1992) Effects of TNF-α and phorbol ester on human surfactant protein and MnSOD gene transcription in vitro. Am J Physiol Lung Cell Mol Physiol 6:L688–L693Google Scholar
  43. 43.
    Solaroglu I, Tsubokawa T, Cahill J, Zhang JH (2006) Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat. Neuroscience 143:965–974CrossRefPubMedGoogle Scholar
  44. 44.
    Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck H-H, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Rüther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Sirén A-L (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8:495–505PubMedGoogle Scholar
  45. 45.
    Hama T, Kushima Y, Miyamoto M, Kubota M, Takei N, Hatanaka H (1991) Interleukin-6 improves the survival of mesencephalic catecholaminergic and septal cholinergic neurons from postnatal, two-week-old rats in cultures. Neuroscience 40:445–452CrossRefPubMedGoogle Scholar
  46. 46.
    Herrmann O, Tarabin V, Suzuki S, Attigah N, Coserea I, Schneider A, Vogel J, Prinz S, Schwab S, Monyer H, Brombacher F, Schwaninger M (2003) Regulation of body temperature and neuroprotection by endogenous interleukin-6 in cerebral ischemia. J Cereb Blood Flow Metab 23:406–415CrossRefPubMedGoogle Scholar
  47. 47.
    Komine-Kobayashi M, Zhang N, Liu M, Tanaka R, Hara H, Osaka A, Mochizuki H, Mizuno Y, Urabe T (2006) Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab 26:402–413CrossRefPubMedGoogle Scholar
  48. 48.
    Kretz A, Happold CJ, Marticke JK, Isenmann S (2005) Erythropoietin promotes regeneration of adult CNS neurons via Jak2/Stat3 and PI3K/AKT pathway activation. Mol Cell Neurosci 29:569–579CrossRefPubMedGoogle Scholar
  49. 49.
    Kumral A, Genc S, Ozer E, Yilmaz O, Gokmen N, Koroglu TF, Duman N, Genc K, Ozkan H (2006) Erythropoietin downregulates Bax and DP5 proapoptotic gene expression in neonatal hypoxic-ischemic brain injury. Biol Neonate 89:205–210CrossRefPubMedGoogle Scholar
  50. 50.
    Kushima Y, Hatanaka H (1992) Interleukin-6 and leukemia inhibitory factor promote the survival of acetylcholinesterase-positive neurons in culture from embryonic rat spinal cord. Neurosci Lett 143:110–114CrossRefPubMedGoogle Scholar
  51. 51.
    Loddick SA, Turnbull AV, Rothwell NJ (1998) Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 18:176–179CrossRefPubMedGoogle Scholar
  52. 52.
    MacLaren RE, Buch PK, Smith AJ, Balaggan KS, MacNeil A, Taylor JS, Osborne NN, Ali RR (2006) CNTF gene transfer protects ganglion cells in rat retinae undergoing focal injury and branch vessel occlusion. Exp Eye Res 83:1118–1127CrossRefPubMedGoogle Scholar
  53. 53.
    Solaroglu I, Solaroglu A, Kaptanoglu E, Dede S, Haberal A, Beskonakli E, Kilinc K (2003) Erythropoietin prevents ischemia-reperfusion from inducing oxidative damage in fetal rat brain. Childs Nerv Syst 19:19–22PubMedGoogle Scholar
  54. 54.
    Suzuki S, Yamashita T, Tanaka K, Hattori H, Sawamoto K, Okano H, Suzuki N (2005) Activation of cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 attenuates ischemic brain injury in rats. J Cereb Blood Flow Metab 25:685–693CrossRefPubMedGoogle Scholar
  55. 55.
    Jin K, Sun Y, Xie L, Childs J, Mao XO, Greenberg DA (2004) Post-ischemic administration of heparin-binding epidermal growth factor-like growth factor (HB-EGF) reduces infarct size and modifies neurogenesis after focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 24:399–408CrossRefPubMedGoogle Scholar
  56. 56.
    Labelle C, Leclerc N (2000) Exogenous BDNF, NT-3 and NT-4 differentially regulate neurite outgrowth in cultured hippocampal neurons. Dev Brain Res 123:1–11CrossRefGoogle Scholar
  57. 57.
    Nakatomi H, Kuriu T, Okabe S, Yamamoto S-i, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M (2002) Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110:429–441CrossRefPubMedGoogle Scholar
  58. 58.
    Schicho R, Schuligoi R, Sirinathsinghji DJS, Donnerer J (1999) Increased expression of GAP-43 in small sensory neurons after stimulation by NGF indicative of neuroregeneration in capsaicin-treated rats. Regul Pept 83:87–95CrossRefPubMedGoogle Scholar
  59. 59.
    Vincent AM, Mobley BC, Hiller A, Feldman EL (2004) IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiol Dis 16:407–416CrossRefPubMedGoogle Scholar
  60. 60.
    Yadav A, Kalita A, Dhillon S, Banerjee K (2005) JAK/STAT3 pathway is involved in survival of neurons in response to insulin-like growth factor and negatively regulated by suppressor of cytokine signaling-3. J Biol Chem 280:31830–31840CrossRefPubMedGoogle Scholar
  61. 61.
    Yamashita K, Wiessner C, Lindholm D, Thoenen H, Hossmann K-A (1997) Post-occlusion treatment with BDNF reduces infarct size in a model of permanent occlusion of the middle cerebral artery in rat. Metab Brain Dis 12:271–280PubMedGoogle Scholar
  62. 62.
    Hurn PD, Macrae IM (2000) Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab 20:631–652CrossRefPubMedGoogle Scholar
  63. 63.
    Rusa R, Alkayed NJ, Crain BJ, Traystman RJ, Kimes AS, London ED, Klaus JA, Hurn PD (1999) 17β-estradiol reduces stroke injury in estrogen-deficient female animals. Stroke 30:1665–1670PubMedGoogle Scholar
  64. 64.
    Levy DE, Darnell JE Jr (2002) STATs: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662CrossRefPubMedGoogle Scholar
  65. 65.
    Shyu W-C, Lin S-Z, Chiang M-F, Chen D-C, Su C-Y, Wang H-J, Liu R-S, Tsai C-H, Li H (2008) Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke. J Clin Invest 118:133–148CrossRefPubMedGoogle Scholar
  66. 66.
    Dziennis S, Alkayed NJ (2008) Role of signal transducer and activator of transcription 3 in neuronal survival and regeneration. Rev Neurosci 19:341–361PubMedGoogle Scholar
  67. 67.
    Yamashita T, Sawamoto K, Suzuki S, Suzuki N, Adachi K, Kawase T, Mihara M, Ohsugi Y, Abe K, Okano H (2005) Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons. J Neurochem 94:459–468CrossRefPubMedGoogle Scholar
  68. 68.
    Bedard K, Krause K-H (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313CrossRefPubMedGoogle Scholar
  69. 69.
    Tejada-Simon MV, Serrano F, Villasana LE, Kanterewicz BI, Wu G-Y, Quinn MT, Klann E (2005) Synaptic localization of a functional NADPH oxidase in the mouse hippocampus. Mol Cell Neurosci 29:97–106CrossRefPubMedGoogle Scholar
  70. 70.
    Kim MJ, Shin K-S, Chung Y-B, Jung KW, Cha CI, Shin DH (2005) Immunohistochemical study of p47Phox and gp91Phox distributions in rat brain. Brain Res 1040:178–186CrossRefPubMedGoogle Scholar
  71. 71.
    Infanger DW, Sharma RV, Davisson RL (2006) NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 8:1583–1596CrossRefPubMedGoogle Scholar
  72. 72.
    Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189CrossRefPubMedGoogle Scholar
  73. 73.
    Ray R, Shah AM (2005) NADPH oxidase and endothelial cell function. Clin Sci 109:217–226CrossRefPubMedGoogle Scholar
  74. 74.
    Hordijk PL (2006) Regulation of NADPH oxidases. The role of Rac proteins. Circ Res 98:453–462CrossRefPubMedGoogle Scholar
  75. 75.
    Miyano K, Sumimoto H (2007) Role of the small GTPase Rac in p22phox-dependent NADPH oxidases. Biochimie 89:1133–1144CrossRefPubMedGoogle Scholar
  76. 76.
    Chen H, Song YS, Chan PH (2009) Inhibition of NADPH oxidase is neuroprotective after ischemia–reperfusion. J Cereb Blood Flow Metab 29:1262–1272CrossRefPubMedGoogle Scholar
  77. 77.
    Suh SW, Shin BS, Ma H, Van Hoecke M, Brennan AM, Yenari MA, Swanson RA (2008) Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol 64:654–663CrossRefPubMedGoogle Scholar
  78. 78.
    Li B, Guo Y-S, Sun M-M, Dong H, Wu S-Y, Wu D-X, Li C-Y (2008) The NADPH oxidase is involved in lipopolysaccharide-mediated motor neuron injury. Brain Res 1226:199–208CrossRefPubMedGoogle Scholar
  79. 79.
    Wu D-C, Ré DB, Nagai M, Ischiropoulos H, Przedborski S (2006) The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis in mice. Proc Natl Acad Sci USA 103:12132–12137CrossRefPubMedGoogle Scholar
  80. 80.
    Di Virgilio F (2004) New pathways for reactive oxygen species generation in inflammation and potential novel pharmacological targets. Curr Pharm Des 10:1647–1652CrossRefPubMedGoogle Scholar
  81. 81.
    Block ML (2008) NADPH oxidase as a therapeutic target in Alzheimer's disease. BMC Neurosci 9(Suppl 2):S8. doi:10.1186/1471-2202-1189-S1182-S1188 CrossRefPubMedGoogle Scholar
  82. 82.
    Zekry D, Epperson TK, Krause K-H (2003) A role for NOX NADPH oxidases in Alzheimer's disease and other types of dementia? IUBMB Life 55:307–313CrossRefPubMedGoogle Scholar
  83. 83.
    Maier CM, Narasimhan P, Song YS, Chan PH (2007) NADPH oxidase expression following cerebral ischemia-reperfusion in SOD2-KO mice may be associated with endothelial cell damage. Presentation No. 447.9. Neuroscience 2007, November 3–7, San DiegoGoogle Scholar
  84. 84.
    Narasimhan P, Liu J, Song YS, Massengale JL, Chan PH (2009) VEGF stimulates the ERK 1/2 signaling pathway and apoptosis in cerebral endothelial cells after ischemic conditions. Stroke 40:1467–1473CrossRefPubMedGoogle Scholar
  85. 85.
    Kim GS, Jung JE, Niizuma K, Chan PH (2009) CK2 is a novel negative regulator of NADPH oxidase and a neuroprotectant in mice after cerebral ischemia. J Neurosci 29:14779–14789CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2010

Authors and Affiliations

  • Joo Eun Jung
    • 1
    • 2
    • 3
  • Gab Seok Kim
    • 1
    • 2
    • 3
  • Hai Chen
    • 1
    • 2
    • 3
  • Carolina M. Maier
    • 1
    • 2
    • 3
  • Purnima Narasimhan
    • 1
    • 2
    • 3
  • Yun Seon Song
    • 1
    • 2
    • 3
  • Kuniyasu Niizuma
    • 1
    • 2
    • 3
  • Masataka Katsu
    • 1
    • 2
    • 3
  • Nobuya Okami
    • 1
    • 2
    • 3
  • Hideyuki Yoshioka
    • 1
    • 2
    • 3
  • Hiroyuki Sakata
    • 1
    • 2
    • 3
  • Christina E. Goeders
    • 1
    • 2
    • 3
  • Pak H. Chan
    • 1
    • 2
    • 3
  1. 1.Department of NeurosurgeryStanford University School of MedicineStanfordUSA
  2. 2.Department of Neurology and Neurological SciencesStanford University School of MedicineStanfordUSA
  3. 3.Program in NeurosciencesStanford University School of MedicineStanfordUSA

Personalised recommendations