NADPH oxidases as therapeutic targets in ischemic stroke

Cellular and Molecular Life Sciences

Volumn 69, Issue 14, 2012, Pages 2345-2363

  Kahles, Timo ^a   Brandes, Ralf P ^a  

^a GOETHE UNIVERSITY MEDICAL SCHOOL   (Germany)

Author keywords

Brain; Ischemia; NADPH oxidase; Reactive oxygen species; Reperfusion; Stroke

Indexed keywords

4 (2 AMINOETHYL)BENZENESULFONYL FLUORIDE; APOCYNIN; ATORVASTATIN; CANDESARTAN; CASEIN KINASE II; CELASTROL; DIPHENYLIODONIUM SALT; GP91DS TAT PEPTIDE; OXIDOREDUCTASE INHIBITOR; OXYGEN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PR 39; PROTEIN KINASE C INHIBITOR; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 1; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 2; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 4; RHO KINASE INHIBITOR; SYNTHETIC PEPTIDE; UNCLASSIFIED DRUG; VAS 2870;

BLOOD BRAIN BARRIER; BRAIN BLOOD VESSEL; BRAIN INJURY; BRAIN ISCHEMIA; DRUG MECHANISM; DRUG TARGETING; ENZYME ACTIVITY; ENZYME LOCALIZATION; HUMAN; ISCHEMIC PRECONDITIONING; MOLECULAR PATHOLOGY; NONHUMAN; OXYGEN THERAPY; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; BLOOD-BRAIN BARRIER; ENZYME INHIBITORS; HUMANS; NADPH OXIDASE; OXIDATION-REDUCTION; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES; REPERFUSION INJURY; STROKE;

EID: 84864330120     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-012-1011-8     Document Type: Review

References (204)

1. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, De SG, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J (2011) Heart disease and stroke statistics-2011 update: a report from the American Heart Association. Circulation 123:e18-e209. doi:10.1161/CIR. 0b013e3182009701
2. World Health Organization (WHO) (2004) The atlas of heart disease and stroke. World Health Organization, Geneva
3. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D (2008) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359:1317-1329
4. Molina CA (2011) Reperfusion therapies for acute ischemic stroke: current pharmacological and mechanical approaches. Stroke 42:S16-S19. doi:10.1161/STROKEAHA.110.598763
5. Soberman RJ (2003) The expanding network of redox signaling: new observations, complexities, and perspectives. J Clin Invest 111:571-574. doi:10.1172/JCI18099 (Pubitemid 36278572)
6. Lambeth JD (2007) Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic Biol Med 43:332-347 (Pubitemid 46992767)
7. D'Autreaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8:813-824 (Pubitemid 47462134)
8. Brandes RP (2003) Role of NADPH oxidases in the control of vascular gene expression. Antioxid Redox Signal 5:803-811 (Pubitemid 37462064)
9. Stadtman ER, Levine RL (2003) Free radical-mediated oxidation of free amino acids and amino acid residues in proteins. Amino Acids 25:207-218. doi:10.1007/s00726-003-0011-2 (Pubitemid 38043943)
10. Saran M (2003) To what end does nature produce superoxide? NADPH oxidase as an autocrine modifier of membrane phospholipids generating paracrine lipid messengers. Free Radic Res 37:1045-1059 (Pubitemid 37265327)
11. Marnett LJ, Plastaras JP (2001) Endogenous DNA damage and mutation. Trends Genet 17:214-221. doi:S0168-9525(01)02239-9 (Pubitemid 32239541)
12. Adibhatla RM, Hatcher JF (2010) Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 12:125-169. doi:10.1089/ARS.2009.2668
13. Armstrong JS, Khdour O, Hecht SM (2010) Does oxidative stress contribute to the pathology of Friedreich's ataxia? Aradical question. FASEB J 24:2152-2163. doi:10.1096/fj.09-143222
14. Simonyi A, He Y, Sheng W, Sun AY, Wood WG, Weisman GA, Sun GY (2010) Targeting NADPH oxidase and phospholipases A2 in Alzheimer's disease. Mol Neurobiol 41:73-86. doi: 10.1007/s12035-010-8107-7
15. Waldbaum S, Patel M (2010) Mitochondria, oxidative stress, and temporal lobe epilepsy. Epilepsy Res 88:23-45. doi:10.1016/j.eplepsyres.2009.09.020
16. Ghafourifar P, Mousavizadeh K, Parihar MS, Nazarewicz RR, Parihar A, Zenebe WJ (2008) Mitochondria in multiple sclerosis. Front Biosci 13:3116-3126. doi:2913 (Pubitemid 351589223)
17. Sorce S, Krause KH (2009) NOX enzymes in the central nervous system: from signaling to disease. Antioxid Redox Signal 11:2481-2504
18. Nelson CW, Wei EP, Povlishock JT, Kontos HA, Moskowitz MA (1992) Oxygen radicals in cerebral ischemia. Am J Physiol 263:H1356-H1362
19. Gursoy-Ozdemir Y, Can A, Dalkara T (2004) Reperfusioninduced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke 35:1449-1453 (Pubitemid 38697474)
20. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. TrendsNeurosci 22:391-397 (Pubitemid 29453643)
21. Lee JM, Grabb MC, Zipfel GJ, Choi DW (2000) Brain tissue responses to ischemia. J Clin Invest 106:723-731. doi:10.1172/JCI11003
22. Moro MA, Almeida A, Bolanos JP, Lizasoain I (2005) Mitochondrial respiratory chain and free radical generation in stroke. Free Radic Biol Med 39:1291-1304. doi:10.1016/j.freeradbiomed.2005.07.010 (Pubitemid 41540085)
23. Nogawa S, Zhang F, Ross ME, Iadecola C (1997) Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 17:2746-2755 (Pubitemid 27155008)
24. Muir SW, Harrow C, Dawson J, Lees KR, Weir CJ, Sattar N, Walters MR (2008) Allopurinol use yields potentially beneficial effects on inflammatory indices in those with recent ischemic stroke: a randomized, double-blind, placebo-controlled trial. Stroke 39:3303-3307. doi:10.1161/STROKEAHA.108.519793
25. Berry C, Hamilton CA, Brosnan MJ, Magill FG, Berg GA, McMurray JJ, Dominiczak AF (2000) Investigation into the sources of superoxide in human blood vessels: angiotensin II increases superoxide production in human internal mammary arteries. Circulation 101:2206-2212 (Pubitemid 30253051)
26. Dawson J, Quinn T, Walters M (2007) Uric acid reduction: a new paradigm in the management of cardiovascular risk? Curr Med Chem 14:1879-1886 (Pubitemid 47163405)
27. Margaill I, Plotkine M, Lerouet D (2005) Antioxidant strategies in the treatment of stroke. Free Radic Biol Med 39:429-443 (Pubitemid 41021642)
28. Lin Y, Phillis JW (1991) Oxypurinol reduces focal ischemic brain injury in the rat. Neurosci Lett 126:187-190
29. Betz AL, Randall J, Martz D (1991) Xanthine oxidase is not a major source of free radicals in focal cerebral ischemia. Am J Physiol 260:H563-H568
30. Dawson J, Quinn TJ, Harrow C, Lees KR, Walters MR (2009) The effect of allopurinol on the cerebral vasculature of patients with subcortical stroke; a randomized trial. Br J Clin Pharmacol 68:662-668. doi:10.1111/j.1365-2125.2009. 03497.x
31. Fabian RH, Kent TA (1999) Superoxide anion production during reperfusion is reduced by an antineutrophil antibody after prolonged cerebral ischemia. Free Radic Biol Med 26:355-361.doi: S0891-5849(98)00215-9 (Pubitemid 29013467)
32. Kahles T, Luedike P, Endres M, Galla HJ, Steinmetz H, Busse R, Neumann-Haefelin T, Brandes RP (2007) NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 38:3000-3006 (Pubitemid 350035696)
33. Chen H, Yoshioka H, Kim GS, Jung JE, Okami N, Sakata H, Maier CM, Narasimhan P, Goeders CE, Chan PH (2011) Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid Redox Signal 14:1505-1517. doi:10.1089/ars.2010.3576
34. Brandes RP (2005) Triggering mitochondrial radical release: a new function for NADPH oxidases. Hypertension 45:847-848 (Pubitemid 40628925)
35. 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 12:857-863. doi:10.1038/nn.2334
36. O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW (2006) 1,026 experimental treatments in acute stroke. Ann Neurol 59:467-477. doi:10.1002/ana.20741 (Pubitemid 43358067)
37. Kuroda S, Tsuchidate R, Smith ML, Maples KR, Siesjo BK (1999) Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 19:778-787. doi:10.1097/00004647-199907000-00008 (Pubitemid 30159804)
38. Marshall JW, Cummings RM, Bowes LJ, Ridley RM, Green AR (2003) Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke 34:2228-2233. doi:10.1161/01.STR.0000087790.79851.A8 (Pubitemid 37099841)
39. Myint PK, Luben RN, Welch AA, Bingham SA, Wareham NJ, Khaw KT (2008) Plasma vitamin C concentrations predict risk of incident stroke over 10 y in 20 649 participants of the European Prospective Investigation into Cancer Norfolk prospective population study. Am J Clin Nutr 87:64-69 87/1/64
40. Riemersma RA, Wood DA, Macintyre CC, Elton RA, Gey KF, Oliver MF (1991) Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet 337:1-50140-6736(91)93327-6
41. Singh RB, Ghosh S, Niaz MA, Singh R, Beegum R, Chibo H, Shoumin Z, Postiglione A (1995) Dietary intake, plasma levels of antioxidant vitamins, and oxidative stress in relation to coronary artery disease in elderly subjects. Am J Cardiol 76:1233-1238 S0002914999803488
42. Diener HC, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Shuaib A, Ashwood T, Wasiewski W, Alderfer V, Hardemark HG, Rodichok L (2008) NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials. Stroke 39:1751-1758. doi:10.1161/STROKEAHA.107.503334
43. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2008) Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev 16:CD007176. doi:10.1002/14651858.CD007176 (Pubitemid 351807478)
44. Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142:37-46 0000605-200501040-00110
45. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ (2003) Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 361:2017-2023. doi:10.1016/S0140-6736(03)13637-9 (Pubitemid 36695043)
46. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245-313 (Pubitemid 46209993)
47. Mun-Bryce S, Rosenberg GA (1998) Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab 18:1163-1172. doi:10.1097/00004647-199811000-00001 (Pubitemid 28509829)
48. Zhao BQ, Wang S, Kim HY, Storrie H, Rosen BR, Mooney DJ, Wang X, Lo EH (2006) Role of matrix metalloproteinases indelayed cortical responses after stroke. Nat Med 12:441-445. doi:10.1038/nm1387
49. Kunz A, Park L, Abe T, Gallo EF, Anrather J, Zhou P, Iadecola C (2007) Neurovascular protection by ischemic tolerance: role of nitric oxide and reactive oxygen species. J Neurosci 27:7083-7093 (Pubitemid 47037566)
50. Kawano T, Kunz A, Abe T, Girouard H, Anrather J, Zhou P, Iadecola C (2007) iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury throughperoxynitrite. J Cereb Blood Flow Metab 27:1453-1462 (Pubitemid 47106605)
51. Iadecola C (1997) Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci 20:132-139 (Pubitemid 27086729)
52. Park L, Zhou P, Pitstick R, Capone C, Anrather J, Norris EH, Younkin L, Younkin S, Carlson G, McEwen BS, Iadecola C (2008) Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci USA 105:1347-1352 (Pubitemid 351397056)
53. Park L, Anrather J, Zhou P, Frys K, Pitstick R, Younkin S, Carlson GA, Iadecola C (2005) NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci 25:1769-1777 (Pubitemid 40279282)
54. Block ML (2008) NADPH oxidase as a therapeutic target in Alzheimer's disease. BMC Neurosci 9(2):S8
55. Chrissobolis S, Miller AA, Drummond GR, Kemp-Harper BK, Sobey CG (2011) Oxidative stress and endothelial dysfunction in cerebrovascular disease. Front Biosci 16:1733-1745. doi: 10.2741/3816
56. Girouard H, Park L, Anrather J, Zhou P, Iadecola C (2006) Angiotensin II attenuates endothelium-dependent responses in the cerebral microcirculation through Nox-2-derived radicals. Arterioscler Thromb Vasc Biol 26:826-832 (Pubitemid 43732158)
57. Park L, Anrather J, Girouard H, Zhou P, Iadecola C (2007) Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab 27:1908-1918 (Pubitemid 350129160)
58. Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA (2007) Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J Clin Invest 117:910-918 (Pubitemid 46556747)
59. Chrissobolis S, Faraci FM (2008) The role of oxidative stress and NADPH oxidase in cerebrovascular disease. Trends Mol Med 14:495-502
60. Allen CL, Bayraktutan U (2009) Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke 4:461-470. doi:10.1111/j.1747- 4949.2009.00387.x
61. Davi G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482-2494
62. Pun PB, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res: 43:348-364
63. Kahles T, Heumueller S, Brandes RP. NADPH oxidases and blood-brain barrier dysfunction in stroke. In Sauer H, Shah AM, Laurindo FR, eds. Studies on Cardiovascular Disorders. Humana Press, New York, 2010, pp 211-230
64. Hamann GF, Okada Y, del Zoppo GJ (1996) Hemorrhagic transformation and microvascular integrity during focal cerebral ischemia/reperfusion. J Cereb Blood Flow Metab 16:1373-1378 (Pubitemid 26365393)
65. Heo JH, Han SW, Lee SK (2005) Free radicals as triggers of brain edema formation after stroke. Free Radic Biol Med 39:51-70
66. Rosenberg GA, Yang Y (2007) Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 22:E4
67. Ayata C, Ropper AH (2002) Ischaemic brain oedema. J Clin Neurosci 9:113-124. doi:10.1054/jocn.2001.1031 (Pubitemid 34464579)
68. Kuroiwa T, Ting P, Martinez H, Klatzo I (1985) The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol 68:122-129 (Pubitemid 16242137)
69. Gasche Y, Copin JC (2003) Blood-brain barrier pathophysiology and ischaemic brain oedema. Ann Fr Anesth Reanim 22:312-319 (Pubitemid 36995280)
70. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581-1588. doi: 10.1056/NEJM199512143332401
71. Durukan A, Marinkovic I, Strbian D, Pitkonen M, Pedrono E, Soinne L, Abo-Ramadan U, Tatlisumak T (2009) Post-ischemic blood-brain barrier leakage in rats: one-week follow-up by MRI. Brain Res 1280:158-165. doi:10.1016/j.brainres. 2009.05.025
72. Strbian D, Durukan A, Pitkonen M, Marinkovic I, Tatlisumak E, Pedrono E, Abo-Ramadan U, Tatlisumak T (2008) The bloodbrain barrier is continuously open for several weeks following transient focal cerebral ischemia. Neuroscience 153:175-181. doi:10.1016/j.neuroscience.2008.02.012
73. Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67:181-198. doi:10.1016/j.neuron.2010.07.002
74. Fisher M (2009) Pericyte signaling in the neurovascular unit. Stroke 40:S13-S15
75. Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P (2009) Brain endothelial cells and the glio-vascular complex. Cell Tissue Res 335:75-96
76. Chen ZL, Indyk JA, Bugge TH, Kombrinck KW, Degen JL, Strickland S (1999) Neuronal death and blood-brain barrier breakdown after excitotoxic injury are independent processes. J Neurosci 19:9813-9820 (Pubitemid 30226654)
77. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335-344. doi:10.1113/jphysiol.2003.049478 (Pubitemid 37321833)
78. Siesjo BK, Elmer E, Janelidze S, Keep M, Kristian T, Ouyang YB, Uchino H (1999) Role and mechanisms of secondary mitochondrial failure. Acta Neurochir Suppl 73:7-13
79. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87:779-789. doi:10.1189/jlb.1109766
80. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461-553. doi:10.1152/physrev.00011.2010
81. Cheret C, Gervais A, Lelli A, Colin C, Amar L, Ravassard P, Mallet J, Cumano A, Krause KH, Mallat M (2008) Neurotoxic activation of microglia is promoted by a Nox1-dependent NADPH oxidase. J Neurosci 28:12039-12051
82. Yenari MA, Kauppinen TM, Swanson RA (2010) Microglial activation in stroke: therapeutic targets. Neurotherapeutics 7:378-391. doi:10.1016/j.nurt. 2010.07.005
83. Iadecola C, Zhang F, Xu S, Casey R, Ross ME (1995) Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 15:378-384. doi:10.1038/jcbfm.1995.47
84. Iadecola C, Zhang F, Casey R, Clark HB, Ross ME (1996) Inducible nitric oxide synthase gene expression in vascular cells after transient focal cerebral ischemia. Stroke 27:1373-1380 (Pubitemid 26286171)
85. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315-424 (Pubitemid 46217686)
86. Ryu JK, McLarnon JG (2006) Minocycline or iNOS inhibition block 3-nitrotyrosine increases and blood-brain barrier leakiness in amyloid beta-peptide-injected rat hippocampus. Exp Neurol 198:552-557. doi:10.1016/j.expneurol.2005.12.016
87. Yenari MA, Xu L, Tang XN, QiaoY, Giffard RG(2006) Microglia potentiate damage to blood-brain barrier constituents: improvement by minocycline in vivo and in vitro. Stroke 37:1087-1093. doi:10.1161/01.STR.0000206281.77178.ac
88. Strbian D, Karjalainen-Lindsberg ML, Tatlisumak T, Lindsberg PJ (2006) Cerebral mast cells regulate early ischemic brain swelling and neutrophil accumulation. J Cereb Blood Flow Metab 26:605-612. doi:10.1038/sj.jcbfm.9600228
89. Kim GW, Lewen A, Copin J, Watson BD, Chan PH (2001) The cytosolic antioxidant, copper/zinc superoxide dismutase, attenuates blood-brain barrier disruption and oxidative cellular injury after photothrombotic cortical ischemia in mice. Neuroscience 105:1007-1018 (Pubitemid 32786813)
90. Lehner C, Gehwolf R, Tempfer H, Krizbai I, Hennig B, Bauer HC, Bauer H (2011) Oxidative stress and blood-brain barrier dysfunction under particular consideration of matrix metalloproteinases. Antioxid Redox Signal 15:1305-1323. doi: 10.1089/ars.2011.3923
91. Jin L, Ying Z, Webb RC (2004) Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta. Am J Physiol Heart Circ Physiol 287:H1495-H1500 (Pubitemid 39313251)
92. Diekmann D, Abo A, Johnston C, Segal AW, Hall A (1994) Interaction of Rac with p67phox and regulation of phagocytic NADPH oxidase activity. Science 265:531-533
93. Schreibelt G, KooijG, Reijerkerk A, van DR, Gringhuis SI, van der PS, Weksler BB, Romero IA, Couraud PO, Piontek J, Blasig IE, Dijkstra CD, Ronken E, De Vries HE (2007) Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling. FASEB J 21:3666-3676 (Pubitemid 350075154)
94. Kuhlmann CR, Tamaki R, Gamerdinger M, Lessmann V, Behl C, Kempski OS, Luhmann HJ (2007) Inhibition of the myosin light chain kinase prevents hypoxia-induced blood-brain barrier disruption. J Neurochem 102:501-507. doi:10.1111/j.1471-4159.2007.04506.x (Pubitemid 47000593)
95. Haorah J, Ramirez SH, Schall K, Smith D, Pandya R, Persidsky Y (2007) Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction. J Neurochem 101:566-576 (Pubitemid 46525283)
96. Woodcock SA, Rooney C, Liontos M, Connolly Y, Zoumpourlis V, Whetton AD, Gorgoulis VG, Malliri A (2009) SRC-induced disassembly of adherens junctions requires localized phosphorylation and degradation of the rac activator tiam1. Mol Cell 33:639-653
97. Miller AA, Drummond GR, Sobey CG (2006) Novel isoforms of NADPH-oxidase in cerebral vascular control. Pharmacol Ther 111:928-948 (Pubitemid 44160524)
98. Ray R, Murdoch CE, Wang M, Santos CX, Zhang M, Alom-Ruiz S, Anilkumar N, Ouattara A, Cave AC, Walker SJ, Grieve DJ, Charles RL, Eaton P, Brewer AC, Shah AM (2011) Endothelial nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo. Arterioscler Thromb Vasc Biol 31:1368-1376. doi:10.1161/ATVBAHA.110.219238
99. Nisimoto Y, Jackson HM, Ogawa H, Kawahara T, Lambeth JD (2010) Constitutive NADPH-dependent electron transferase activity of the Nox4 dehydrogenase domain. Biochemistry 49:2433-2442. doi:10.1021/bi9022285
100. Martyn KD, Frederick LM, von LK, Dinauer MC, Knaus UG (2006) Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal 18:69-82. doi:10.1016/j.cellsig.2005.03.023 (Pubitemid 41415716)
101. Helmcke I, Heumuller S, Tikkanen R, Schroder K, Brandes RP (2009) Identification of structural elements in Nox1 and Nox4 controlling localization and activity. Antioxid Redox Signal 11:1279-1287. doi:10.1089/ARS.2008.2383
102. Kawahara T, Jackson HM, Smith SM, Simpson PD, Lambeth JD (2011) Nox5 forms a functional oligomer mediated by selfassociation of its dehydrogenase domain. Biochemistry 50:2013-2025. doi:10.1021/bi1020088
103. Kawahara T, Quinn MT, Lambeth JD (2007) Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox/ Duox) family of enzymes. BMC Evol Biol 7:109
104. Leto TL, Morand S, Hurt D, Ueyama T (2009) Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxid Redox Signal 11:2607-2619. doi:10.1089/ARS.2009.2637
105. Paffenholz R, Bergstrom RA, Pasutto F, Wabnitz P, Munroe RJ, Jagla W, Heinzmann U, Marquardt A, Bareiss A, Laufs J, Russ A, Stumm G, Schimenti JC, Bergstrom DE (2004) Vestibular defects in head-tilt mice result from mutations in Nox3, encoding an NADPH oxidase. Genes Dev 18:486-491 (Pubitemid 38372805)
106. Infanger DW, Sharma RV, Davisson RL (2006) NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 8:1583-1596 (Pubitemid 44726333)
107. Ago T, Kitazono T, Kuroda J, Kumai Y, Kamouchi M, Ooboshi H, Wakisaka M, Kawahara T, Rokutan K, Ibayashi S, Iida M (2005) NAD(P)H oxidases in rat basilar arterial endothelial cells. Stroke 36:1040-1046 (Pubitemid 40629300)
108. Ago T, Kitazono T, Ooboshi H, Iyama T, Han YH, Takada J, Wakisaka M, Ibayashi S, Utsumi H, Iida M (2004) Nox4 as the major catalytic component of an endothelial NAD(P)H oxidase. Circulation 109:227-233. doi:10.1161/01.CIR. 0000105680.92873.70 (Pubitemid 38114144)
109. Kahles T, Kohnen A, Heumueller S, Rappert A, Bechmann I, Liebner S, Wittko IM, Neumann-Haefelin T, Steinmetz H, Schroeder K, Brandes RP (2010) NADPH oxidase Nox1 contributes to ischemic injury in experimental stroke in mice.Neurobiol Dis 40:185-192. doi:10.1016/j.nbd.2010.05.023
110. Erdos B, Snipes JA, Tulbert CD, Katakam P, Miller AW, Busija DW (2006) Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production. Am J Physiol Heart Circ Physiol 290:H1264-H1270. doi:10.1152/ajpheart.00804.2005
111. Paravicini TM, Chrissobolis S, Drummond GR, Sobey CG (2004) Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo. Stroke 35:584-589 (Pubitemid 38174454)
112. Kim DE, Suh YS, Lee MS, Kim KY, Lee JH, Lee HS, Hong KW, Kim CD (2002) Vascular NAD(P)H oxidase triggers delayed cerebral vasospasm after subarachnoid hemorrhage in rats. Stroke 33:2687-2691 (Pubitemid 35266442)
113. Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, Iadecola C (2004) Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res 95:1019-1026. doi:10.1161/01.RES.0000148637. 85595.c5 (Pubitemid 39532332)
114. Miller AA, Drummond GR, De Silva TM, Mast AE, Hickey H, Williams JP, Broughton BR, Sobey CG (2009) NADPH oxidase activity is higher in cerebral versus systemic arteries of four animal species: role of Nox2. Am J Physiol Heart Circ Physiol 296:H220-H225
115. Miller AA, Drummond GR, Mast AE, Schmidt HH, Sobey CG (2007) Effect of gender on NADPH-oxidase activity, expression,and function in the cerebral circulation: role of estrogen.Stroke 38:2142-2149 (Pubitemid 47012281)
116. Miller AA, Drummond GR, Schmidt HH, Sobey CG (2005) NADPH oxidase activity and function are profoundly greater in cerebral versus systemic arteries. Circ Res 97:1055-1062 (Pubitemid 41668919)
117. Miller AA, De Silva TM, Judkins CP, Diep H, Drummond GR, Sobey CG (2010) Augmented superoxide production by Nox2-containing NADPH oxidase causes cerebral artery dysfunction during hypercholesterolemia. Stroke 41:784-789. doi:10.1161/STROKEAHA.109.575365
118. Yoshioka H, Niizuma K, Katsu M, Okami N, Sakata H, Kim GS, Narasimhan P, Chan PH (2010) NADPH oxidase mediates striatal neuronal injury after transient global cerebral ischemia.J Cereb Blood Flow Metab 31:868-880. doi:10.1038/jcbfm.2010.166
119. Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M, Barit D, Schwarz T, Geis C, Kraft P, Barthel K, Schuhmann MK, Herrmann AM, Meuth SG, Stoll G, Meurer S,Schrewe A, Becker L, Gailus-Durner V, Fuchs H, Klopstock T, de Angelis MH, Jandeleit-Dahm K, Shah AM, Weissmann N, Schmidt HH (2010) Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol 8(9):e100047. doi:10.1371/journal.pbio.1000479
120. Liu W, Sood R, Chen Q, Sakoglu U, Hendren J, Cetin O, Miyake M, Liu KJ (2008) Normobaric hyperoxia inhibits NADPH oxidase-mediated matrix metalloproteinase-9 induction in cerebral microvessels in experimental stroke. J Neurochem 107:1196-1205
121. De Silva TM, Broughton BR, Drummond GR, Sobey CG, Miller AA (2009) Gender influences cerebral vascular responses to angiotensin II through Nox2-derived reactive oxygen species. Stroke 40:1091-1097
122. Vallet P, Charnay Y, Steger K, Ogier-Denis E, Kovari E, Herrmann F, Michel JP, Szanto I (2005) Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia. Neuroscience 132:233-238 (Pubitemid 40417898)
123. Miller AA, Dusting GJ, Roulston CL, Sobey CG (2006) NADPHoxidaseactivity is elevated in penumbral and non-ischemic cerebral arteries following stroke. Brain Res 1111:111-116 (Pubitemid 44331177)
124. del Zoppo GJ, Schmid-Schonbein GW, Mori E, Copeland BR, Chang CM (1991) Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22:1276-1283
125. Zhang RL, Chopp M, Li Y, Zaloga C, Jiang N, Jones ML, Miyasaka M, Ward PA (1994) Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 44:1747-1751 (Pubitemid 24286659)
126. Zhang RL, Chopp M, Jiang N, Tang WX, Prostak J, Manning AM, Anderson DC (1995) Anti-intercellular adhesion molecule-antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 26:1438-1442
127. Matsuo Y, Kihara T, Ikeda M, Ninomiya M, Onodera H, Kogure K (1995) Role of neutrophils in radical production during ischemia and reperfusion of the rat brain: effect of neutrophil depletion on extracellular ascorbyl radical formation. J Cereb Blood Flow Metab 15:941-947. doi:10.1038/jcbfm.1995.119
128. Chen H, Chopp M, Zhang RL, Bodzin G, Chen Q, Rusche JR, Todd RF III (1994) Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 35:458-463. doi:10.1002/ana.410350414 (Pubitemid 24107854)
129. Hartl R, Schurer L, Schmid-Schonbein GW, del Zoppo GJ (1996) Experimental antileukocyte interventions in cerebral ischemia. J Cereb Blood Flow Metab 16:1108-1119. doi:10.1097/00004647-199611000-00004 (Pubitemid 26365361)
130. Walder CE, Green SP, Darbonne WC, Mathias J, Rae J, Dinauer MC, Curnutte JT, Thomas GR (1997) Ischemic stroke injury isreduced in mice lacking a functional NADPH oxidase. Stroke 28:2252-2258 (Pubitemid 27497931)
131. Abramov AY, Scorziello A, Duchen MR (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 27:1129-1138 (Pubitemid 46203321)
132. Doverhag C, Keller M, Karlsson A, Hedtjarn M, Nilsson U, Kapeller E, Sarkozy G, Klimaschewski L, Humpel C, Hagberg H, Simbruner G, Gressens P, Savman K (2008) Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice. Neurobiol Dis 31:133-144 (Pubitemid 351833142)
133. Chen H, Song YS, Chan PH (2009) Inhibition of NADPH oxidase is neuroprotective after ischemia-reperfusion. J Cereb Blood Flow Metab 29:1262-1272. doi:10.1038/jcbfm.2009.47
134. Chen H, Kim GS, Okami N, Narasimhan P, Chan PH (2011) NADPH oxidase is involved in post-ischemic brain inflammation. Neurobiol Dis 42:341-348. doi:10.1016/j.nbd.2011.01.027
135. Brait VH, Jackman KA, Walduck AK, Selemidis S, Diep H, Mast AE, Guida E, Broughton BR, Drummond GR, Sobey CG (2010) Mechanisms contributing to cerebral infarct size after stroke: gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J Cereb Blood Flow Metab 30:1306-1317. doi:10.1038/jcbfm.2010.14
136. Jackman KA, Miller AA, De Silva TM, Crack PJ, Drummond GR, Sobey CG (2009) Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice. Br J Pharmacol 156:680-688
137. Suh SW, Shin BS, Ma H, Van HM, Brennan AM, Yenari MA, Swanson RA (2008) Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol 64:654-663
138. Jin R, Song Z, Yu S, Piazza A, Nanda A, Penninger JM, GrangerDN, Li G (2011) Phosphatidylinositol-3-kinase gamma plays a central role in blood-brain barrier dysfunction in acute experimental stroke. Stroke 42:2033-2044. doi:10.1161/STROKEAHA.110.601369
139. Jackman KA, Miller AA, Drummond GR, Sobey CG (2009) Importance of NOX1 for angiotensin II-induced cerebrovascular superoxide production and cortical infarct volume following ischemic stroke. Brain Res 1286:215-220. doi:10.1016/j.brainres.2009.06.056
140. Heumuller S, Wind S, Barbosa-Sicard E, Schmidt HH, Busse R, Schroder K, Brandes RP (2008) Apocynin is not an inhibitor of vascular NADPH oxidases but an antioxidant. Hypertension 51:211-217 (Pubitemid 351159930)
141. Williams HC, Griendling KK (2007) NADPH oxidase inhibitors: new antihypertensive agents? J Cardiovasc Pharmacol 50:9-16 (Pubitemid 47220441)
142. Tang XN, Cairns B, Cairns N, Yenari MA (2008) Apocynin improves outcome in experimental stroke with a narrow dose range. Neuroscience 154:556-562
143. Tang LL, Ye K, Yang XF, Zheng JS (2007) Apocynin attenuates cerebral infarction after transient focal ischaemia in rats. J Int Med Res 35:517-522 (Pubitemid 47261114)
144. Kelly KA, Li X, Tan Z, VanGilder RL, Rosen CL, Huber JD (2009) NOX2 inhibition with apocynin worsens stroke outcome in aged rats. Brain Res 1292:165-172. doi:10.1016/j.brainres.2009.07.052
145. Murotomi K, Takagi N, Takeo S, Tanonaka K (2011) NADPH oxidase-mediated oxidative damage to proteins in the postsynaptic density after transient cerebral ischemia and reperfusion. Mol Cell Neurosci 46:681-688. doi:10.1016/j.mcn.2011.01.009
146. Genovese T, Mazzon E, Paterniti I, Esposito E, Bramanti P, Cuzzocrea S (2011) Modulation of NADPH oxidase activation in cerebral ischemia/reperfusion
147. Xie H, Ray PE, Short BL (2005) NF-kappaB activation plays a role in superoxide-mediated cerebral endothelial dysfunction after hypoxia/ reoxygenation. Stroke 36:1047-1052. doi: 10.1161/01.STR.0000157664.34308.cc (Pubitemid 40629301)
148. Wind S, Beuerlein K, Eucker T, Muller H, Scheurer P, Armitage ME, Ho H, Schmidt HH, Wingler K (2010) Comparative pharmacology of chemically distinct NADPH oxidase inhibitors. Br J Pharmacol 161:885-898. doi:10.1111/j.1476-5381. 2010.00920.x
149. Hong H, Zeng JS, Kreulen DL, Kaufman DI, Chen AF (2006) Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke. Am J Physiol Heart Circ Physiol 291:H2210-H2215
150. Vecchione C, Brandes RP (2002) Withdrawal of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors elicits oxidative stress and induces endothelial dysfunction in mice. Circ Res 91:173-179 (Pubitemid 34827229)
151. Gertz K, Laufs U, Lindauer U, Nickenig G, Bohm M, Dirnagl U, Endres M (2003) Withdrawal of statin treatment abrogates stroke protection in mice. Stroke 34:551-557 (Pubitemid 36206363)
152. Raz L, Zhang QG, Zhou CF, Han D, Gulati P, Yang LC, Yang F, Wang RM, Brann DW (2010) Role of Rac1 GTPase in NADPH oxidase activation and cognitive impairment following cerebral ischemia in the rat. PLoS One 5:e12606. doi:10.1371/journal.pone.0012606
153. Kusaka I, Kusaka G, Zhou C, Ishikawa M, Nanda A, Granger DN, Zhang JH, Tang J (2004) Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. Am J Physiol Heart Circ Physiol 286:H2442-H2451 (Pubitemid 38685263)
154. Griendling KK, Ushio-Fukai M (2000) Reactive oxygen species as mediators of angiotensin II signaling. Regul Pept 91:21-27
155. Matsuno K, Yamada H, Iwata K, Jin D, Katsuyama M, Matsuki M, Takai S, Yamanishi K, Miyazaki M, Matsubara H, Yabe-Nishimura C (2005) Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice. Circulation 112:2677-2685 (Pubitemid 41532605)
156. Gavazzi G, Deffert C, Trocme C, Schappi M, Herrmann FR, Krause KH (2007) NOX1 deficiency protects from aortic dissection in response to angiotensin II. Hypertension 50:189-196 (Pubitemid 46992019)
157. Saavedra JM, Sanchez-Lemus E, Benicky J (2011) Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: therapeutic implications. Psychoneuroendocrinology 36:1-18. doi:10.1016/j.psyneuen.2010.10.001
158. Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlof B, De KJ, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C, Voigt T, Weber M, Yoon BW (2008) Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 359:1225-1237. doi:10.1056/NEJMoa0804593
159. Sandset EC, Bath PM, Boysen G, Jatuzis D, Korv J, Luders S, Murray GD, Richter PS, Roine RO, Terent A, Thijs V, Berge E (2011) The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebocontrolled, double-blind trial. Lancet 377:741-750. doi: 10.1016/S0140-6736(11)60104-9
160. Anbanandam A, Albarado DC, Tirziu DC, Simons M, Veeraraghavan S (2008) Molecular basis for proline-and arginine-rich peptide inhibition of proteasome. J Mol Biol 384:219-227. doi: 10.1016/j.jmb.2008.09.021
161. Rey FE, Cifuentes ME, Kiarash A, Quinn MT, Pagano PJ (2001) Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. Circ Res 89:408-414 (Pubitemid 34132656)
162. Csanyi G, Cifuentes-Pagano E, Al G, I, Ranayhossaini DJ, Egana L, Lopes LR, Jackson HM, Kelley EE, Pagano PJ (2011) Nox2 B-loop peptide, Nox2ds, specifically inhibits the NADPH oxidase Nox2. Free Radic Biol Med 51:1116-11125. doi: 10.1016/j.freeradbiomed.2011.04.025
163. Shin HK, Salomone S, Ayata C (2008) Targeting cerebrovascular rho-kinase in stroke. Expert Opin Ther Targets 12:1547-1564. doi:10.1517/14728220802539244
164. Shibuya M, Hirai S, Seto M, Satoh S, Ohtomo E (2005) Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial. J Neurol Sci 238:31-39. doi:10.1016/j.jns.2005.06.003 (Pubitemid 41560951)
165. Higashi M, Shimokawa H, Hattori T, Hiroki J, Mukai Y, Morikawa K, Ichiki T, Takahashi S, Takeshita A (2003) Long-term inhibition of rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system. Circ Res 93:767-775. doi:10.1161/01.RES. 0000096650.91688.28 (Pubitemid 37288672)
166. Shin HK, Salomone S, Potts EM, Lee SW, Millican E, Noma K, Huang PL, Boas DA, Liao JK, Moskowitz MA, Ayata C (2007) Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms. J Cereb Blood Flow Metab 27:998-1009. doi:10.1038/sj.jcbfm.9600406 (Pubitemid 46659030)
167. Sayama CM, Liu JK, Couldwell WT (2006) Update on endovascular therapies for cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage. Neurosurg Focus 21:E12 210312 [pii]
168. Shimazu T, Inoue I, Araki N, Asano Y, Sawada M, Furuya D, Nagoya H, Greenberg JH (2005) A peroxisome proliferatoractivated receptor-gamma agonist reduces infarct size in transient but not in permanent ischemia. Stroke 36:353-359. doi:10.1161/01.STR.0000152271.21943.a2 (Pubitemid 40170822)
169. Zhang HL, Xu M, Wei C, Qin AP, Liu CF, Hong LZ, Zhao XY, Liu J, Qin ZH (2011) Neuroprotective effects of pioglitazone in a rat model of permanent focal cerebral ischemia are associated with peroxisome proliferator-activated receptor gamma-mediated suppression of nuclear factor-kappaB signaling pathway. Neuroscience 176:381-395. doi:10.1016/j.neuroscience.2010.12.029
170. Lu X, Murphy TC, Nanes MS, Hart CM (2010) PPAR{gamma} regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-{kappa}B. Am J Physiol Lung Cell Mol Physiol 299:L559-L566. doi:10.1152/ajplung.00090.2010
171. Lee CH, Park OK, Yoo KY, Byun K, Lee B, Choi JH, Hwang IK, Kim YM, Won MH (2011) The role of peroxisome proliferator-activated receptor gamma, and effects of its agonist, rosiglitazone, on transient cerebral ischemic damage. J Neurol Sci 300:120-129. doi:10.1016/j.jns.2010.09.005
172. Ryan MJ, Didion SP, Mathur S, Faraci FM, Sigmund CD (2004) PPAR(gamma) agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice. Hypertension 43:661-666. doi:10.1161/01.HYP. 0000116303.71408.c2 (Pubitemid 38282444)
173. Nakamura T, Yamamoto E, Kataoka K, Yamashita T, Tokutomi Y, Dong YF, Matsuba S, Ogawa H, Kim-Mitsuyama S (2007) Pioglitazone exerts protective effects against stroke in strokeprone spontaneously hypertensive rats, independently of blood pressure. Stroke 38:3016-3022 (Pubitemid 350041562)
174. Beyer AM, Baumbach GL, Halabi CM, Modrick ML, Lynch CM, Gerhold TD, Ghoneim SM, de Lange WJ, Keen HL, Tsai YS, Maeda N, Sigmund CD, Faraci FM (2008) Interference with PPARgamma signaling causes cerebral vascular dysfunction, hypertrophy, and remodeling. Hypertension 51:867-871. doi:10.1161/ HYPERTENSIONAHA.107.103648 (Pubitemid 351654697)
175. Inoue I, Goto S, Matsunaga T, Nakajima T, Awata T, Hokari S, Komoda T, Katayama S (2001) The ligands/activators for eroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+, Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism 50:3-11. doi: S0026049501534198 (Pubitemid 32058541)
176. Ceolotto G, Gallo A, Papparella I, Franco L, Murphy E, Iori E, Pagnin E, Fadini GP, Albiero M, Semplicini A, Avogaro A (2007) Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism. Arterioscler Thromb Vasc Biol 27:2627-2633. doi:10.1161/ATVBAHA.107. 155762 (Pubitemid 350158915)
177. Jaquet V, Marcoux J, Forest E, Leidal KG, McCormick S, Westermaier Y, Perozzo R, Plastre O, Fioraso-Cartier L, Diebold B, Scapozza L, Nauseef WM, Fieschi F, Krause KH, Bedard K (2011) NOX NADPH oxidase isoforms are inhibited by celastrol with a dual mode of action. Br J Pharmacol. 164:507-520. doi:10.1111/j.1476-5381.2011.01439.x
178. Chen G, Zhang X, Zhao M, Wang Y, Cheng X, Wang D, Xu Y, Du Z, Yu X (2011) Celastrol targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent cytotoxicity in tumor cells. BMC Cancer 11:170. doi:10.1186/1471-2407-11-170
179. Seo HR, Seo WD, Pyun BJ, Lee BW, Jin YB, Park KH, Seo EK, Lee YJ, Lee YS (2011) Radiosensitization by celastrol is mediated by modification of antioxidant thiol molecules. Chem Biol Interact. 193:34-42. doi:10.1016/j.cbi. 2011.04.009
180. Morita T (2010) Celastrol: a new therapeutic potential of traditional Chinese medicine. Am J Hypertens 23:821. doi:10.1038/ajh.2010.87
181. Heitzer T, Wenzel U, Hink U, Krollner D, Skatchkov M, Stahl RA, Macharzina R, Brasen JH, Meinertz T, Munzel T (1999) Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: evidence for an involvement of protein kinase C. Kidney Int 55:252-260. doi:10.1046/j.1523-1755.1999.00229.x (Pubitemid 29004257)
182. Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, Li H, Bodenschatz M, August M, Kleschyov AL, Tsilimingas N, Walter U, Forstermann U, Meinertz T, Griendling K, Munzel T (2002) Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90:E58-E65
183. Bright R, Mochly-Rosen D (2005) The role of protein kinase C in cerebral ischemic and reperfusion injury. Stroke 36:2781-2790. doi:10.1161/01.STR. 0000189996.71237.f7
184. 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 29:14779-14789. doi:10.1523/JNEUROSCI.4161-09.2009
185. Wingler K, Hermans J, Schiffers P, Moens A, Paul M, Schmidt H (2011) NOX 1, 2, 4, 5: counting out oxidative stress. Br J Pharmacol 193:34-42. doi:10.1111/j.1476-5381.2011.01249.x
186. Selemidis S, Sobey CG, Wingler K, Schmidt HH, Drummond GR (2008) NADPH oxidases in the vasculature: molecular features, roles in disease and pharmacological inhibition. Pharmacol Ther 120:254-291. doi:10.1016/j. pharmthera.2008.08.005
187. Jaquet V, Scapozza L, Clark R, Krause KH, Lambeth JD (2009) Small Molecule NOX Inhibitors: ROS-generating NADPH oxidases as therapeutic targets. Antioxid Redox Signal 11:2535-2552
188. ten FH, Huntgeburth M, Wingler K, Schnitker J, Baumer AT, Vantler M, Bekhite MM, Wartenberg M, Sauer H, Rosenkranz S (2006) Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation. Cardiovasc Res Res 71:331-341. doi:10.1016/j.cardiores.2006.01. 022
189. Stielow C, Catar RA, Muller G, Wingler K, Scheurer P, Schmidt HH, Morawietz H (2006) Novel Nox inhibitor of oxLDLinduced reactive oxygen species formation in human endothelial cells. Biochem Biophys Res Commun 344:200-205. doi:10.1016/j.bbrc.2006.03.114
190. Singhal AB, Wang X, Sumii T, Mori T, Lo EH (2002) Effects of normobaric hyperoxia in a rat model of focal cerebral ischemiareperfusion. J Cereb Blood Flow Metab 22:861-868. doi:10.1097/00004647-200207000-00011 (Pubitemid 34747603)
191. Liu S, Liu W, Ding W, Miyake M, Rosenberg GA, Liu KJ (2006) Electron paramagnetic resonance-guided normobaric hyperoxia treatment protects the brain by maintaining penumbral oxygenation in a rat model of transient focal cerebral ischemia. J Cereb Blood Flow Metab 26:1274-1284. doi:10.1038/sj.jcbfm.9600277 (Pubitemid 44435242)
192. Tang X, Liu KJ, Ramu J, Chen Q, Li T, Liu W (2010) Inhibition of gp91(phox) contributes towards normobaric hyperoxia afforded neuroprotection in focal cerebral ischemia. Brain Res 1348:174-180. doi:10.1016/j.brainres.2010.05. 082
193. Nonaka Y, Shimazawa M, Yoshimura S, Iwama T, Hara H (2008) Combination effects of normobaric hyperoxia and edaravone on focal cerebral ischemia-induced neuronal damage in mice. Neurosci Lett 441:224-228. doi:10.1016/j.neulet.2008. 06.033
194. Longhi L, Valeriani V, Rossi S, De MM, Egidi M, Stocchetti N (2002) Effects of hyperoxia on brain tissue oxygen tension in cerebral focal lesions. Acta Neurochir Suppl 81:315-317
195. Rossi S, Longhi L, Balestreri M, Spagnoli D, deLeo A, Stocchetti N (2000) Brain oxygen tension during hyperoxia in a swine model of cerebral ischaemia. Acta Neurochir Suppl 76:243-245
196. Rossi S, Stocchetti N, Longhi L, Balestreri M, Spagnoli D, Zanier ER, Bellinzona G (2001) Brain oxygen tension, oxygen supply, and oxygen consumption during arterial hyperoxia in a model of progressive cerebral ischemia. J Neurotrauma 18:163-174. doi:10.1089/08977150150502596 (Pubitemid 32173424)
197. Wang JY, Shen J, Gao Q, Ye ZG, Yang SY, Liang HW, Bruce IC, Luo BY, Xia Q (2008) Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke 39:983-990. doi:10.1161/STROKEAHA.107.499079 (Pubitemid 351619573)
198. Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X, Zhang S (2008) Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke 39:2362-2369. doi:10.1161/STROKEAHA.107.507939
199. Leconte C, Tixier E, Freret T, Toutain J, Saulnier R, Boulouard M, Roussel S, Schumann-Bard P, Bernaudin M (2009) Delayed hypoxic postconditioning protects against cerebral ischemia in the mouse. Stroke 40:3349-3355. doi:10.1161/STROKEAHA.109.557314
200. Gao X, Zhang H, Takahashi T, Hsieh J, Liao J, Steinberg GK, Zhao H (2008) The Akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the MAPK and PKC pathways. J Neurochem 105:943-955. doi:10.1111/j.1471-4159.2008.05218.x (Pubitemid 351562746)
201. Lauzier B, Sicard P, Bouchot O, Delemasure S, Menetrier F, Moreau D, Vergely C, Rochette L (2007) After four hours of cold ischemia and cardioplegic protocol, the heart can still be rescued with postconditioning. Transplantation 84:1474-1482. doi:10.1097/01.tp.0000288637.18796.0e (Pubitemid 350294723)
202. Shen J, Bai XY, Qin Y, Jin WW, Zhou JY, Zhou JP, Yan YG, Wang Q, Bruce IC, Chen JH, Xia Q (2011) Interrupted reperfusion reduces the activation of NADPH oxidase after cerebral I/R injury. Free Radic Biol Med 50:1780-1786. doi:10.1016/j.freeradbiomed.2011.03.028
203. Kunz A, Anrather J, Zhou P, Orio M, Iadecola C (2007) Cyclooxygenase-2 does not contribute to postischemic production of reactive oxygen species. J Cereb Blood Flow Metab 27:545-551
204. Wang Q, Tompkins KD, Simonyi A, Korthuis RJ, Sun AY, Sun GY (2006) Apocynin protects against global cerebral ischemiareperfusion-induced oxidative stress and injury in the gerbil hippocampus. Brain Res 1090:182-189 (Pubitemid 43817927)