NADPH oxidase as a therapeutic target for neuroprotection against ischaemic stroke: Future perspectives

Brain Sciences

Volumn 3, Issue 2, 2013, Pages 561-598

  Mccann, Sarah K ^a,b   Roulston, Carli L ^a,c  

^a ST VINCENT S HOSPITAL   (Australia)

^b FLOREY INSTITUTE OF NEUROSCIENCE AND MENTAL HEALTH   (Australia)

^c UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

Brain injury; Brain repair; Cerebrovascular event; Drug development; Inhibitors; Ischaemic stroke; Nox; Reactive oxygen species

Indexed keywords

APOCYNIN; ATORVASTATIN; CATALASE; DIPHENYLIODONIUM SALT; DISUFENTON SODIUM; DIZOCILPINE; ENZYME INHIBITOR; EXTRACELLULAR SUPEROXIDE DISMUTASE; FISETIN; GELATINASE B; GLUTATHIONE PEROXIDASE; GP91DS TAT; HYDROGEN PEROXIDE; HYPOCHLOROUS ACID; HYPOXIA INDUCIBLE FACTOR 1; PEROXYNITRITE; QUERCETIN; REACTIVE NITROGEN SPECIES; 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; S 17834; SCAVENGER; SUPEROXIDE DISMUTASE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VAS 2870; VASCULOTROPIN; VASCULOTROPIN C;

ANGIOGENESIS; ANTIBACTERIAL ACTIVITY; APOPTOSIS; BLOOD BRAIN BARRIER; BLOOD CLOT LYSIS; BRAIN BLOOD VESSEL; BRAIN INJURY; BRAIN ISCHEMIA; CELL DIFFERENTIATION; CLINICAL TRIAL (TOPIC); DISEASE COURSE; GENE EXPRESSION; GENETIC MANIPULATION; HUMAN; IMMUNOCOMPETENT CELL; IMMUNOHISTOCHEMISTRY; IMMUNOREACTIVITY; INFLAMMATION; NECROSIS; NERVOUS SYSTEM DEVELOPMENT; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; OXIDATIVE STRESS; OXYGEN CONSUMPTION; PATHOPHYSIOLOGY; PHAGOCYTOSIS; PROTEIN EXPRESSION; RECANALIZATION; REPERFUSION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; REVIEW; SIGNAL TRANSDUCTION; TISSUE REGENERATION;

EID: 84910661241     PISSN: None     EISSN: 20763425     Source Type: Journal    
DOI: 10.3390/brainsci3020561     Document Type: Review

References (227)

1. Crossley, N.A.; Sena, E.; Goehler, J.; Horn, J.; van der Worp, B.; Bath, P.M.; Macleod, M.; Dirnagl, U. Empirical evidence of bias in the design of experimental stroke studies: A metaepidemiologic approach. Stroke 2008, 39, 929-934.
2. Dirnagl, U. Bench to bedside: The quest for quality in experimental stroke research. J. Cereb. Blood Flow Metab. 2006, 26, 1465-1478.
3. Green, A.R. Why do neuroprotective drugs that are so promising in animals fail in the clinic? An industry perspective. Clin. Exp. Pharmacol. Physiol. 2002, 29, 1030-1034.
4. Lo, E.H. Experimental models, neurovascular mechanisms and translational issues in stroke research. Br. J. Pharmacol. 2008, 153, S396-S405.
5. Macleod, M.R.; van der Worp, H.B.; Sena, E.S.; Howells, D.W.; Dirnagl, U.; Donnan, G.A. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke 2008, 39, 2824-2829.
6. O'Collins, V.E.; Macleod, M.R.; Donnan, G.A.; Horky, L.L.; van der Worp, B.H.; Howells, D.W. 1,026 experimental treatments in acute stroke. Ann. Neurol. 2006, 59, 467-477.
7. Feuerstein, G.Z.; Chavez, J. Translational medicine for stroke drug discovery: The pharmaceutical industry perspective. Stroke 2009, 40, S121-S125.
8. Feuerstein, G.Z.; Zaleska, M.M.; Krams, M.; Wang, X.; Day, M.; Rutkowski, J.L.; Finklestein, S.P.; Pangalos, M.N.; Poole, M.; Stiles, G.L.; et al. Missing steps in the stair case: A translational medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke. J. Cereb. Blood Flow Metab. 2008, 28, 217-219.
9. Proctor, P.H.; Tamborello, L.P. SAINT-I worked, but the neuroprotectant is not NXY-059. Stroke 2007, 38, e109.
10. Shuaib, A.; Lees, K.R.; Lyden, P.; Grotta, J.; Davalos, A.; Davis, S.M.; Diener, H.C.; Ashwood, T.; Wasiewski, W.W.; Emeribe, U. NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med. 2007, 357, 562-571.
11. Bal-Price, A.; Matthias, A.; Brown, G.C. Stimulation of the NAD(P)H oxidase in activated rat microglia removes nitric oxide but induces peroxynitrite production. J. Neurochem. 2002, 80, 73-80.
12. Schaller, B.; Graf, R. Cerebral ischemia and reperfusion: The pathophysiologic concept as a basis for clinical therapy. J. Cereb. Blood Flow Metab. 2004, 24, 351-371.
13. Pawate, S.; Shen, Q.; Fan, F.; Bhat, N.R. Redox regulation of glial inflammatory response to lipopolysaccharide and interferongamma. J. Neurosci. Res. 2004, 77, 540-551.
14. Miller, A.A.; Dusting, G.J.; Roulston, C.L.; Sobey, C.G. NADPH-oxidase activity is elevated in penumbral and non-ischemic cerebral arteries following stroke. Brain Res. 2006, 1111, 111-116.
15. Park, L.; Anrather, J.; Zhou, P.; Frys, K.; Pitstick, R.; Younkin, S.; Carlson, G.A.; Iadecola, C. NADPH oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J. Neurosci. 2005, 25, 1769-1777.
16. Kleinschnitz, C.; Grund, H.; Wingler, K.; Armitage, M.E.; Jones, E.; Mittal, M.; Barit, D.; Schwarz, T.; Geis, C.; Kraft, P.; et al. Post-stroke inhibition of induced NAD(P)H oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol. 2010, 8, e1000479.
17. McCann, S.K.; Dusting, G.J.; Roulston, C.L. Early increase of Nox4 NAD(P)H oxidase and superoxide generation following endothelin-1-induced stroke in conscious rats. J. Neurosci. Res. 2008, 86, 2524-2534.
18. Vallet, P.; Charnay, Y.; Steger, K.; Ogier-Denis, E.; Kovari, E.; Herrmann, F.; Michel, J.P.; Szanto, I. Neuronal expression of the NAD(P)H oxidase Nox4, and its regulation in mouse experimental brain ischemia. Neuroscience 2005, 132, 233-238.
19. Warner, D.S.; Sheng, H.; Batinic-Haberle, I. Oxidants, antioxidants and the ischemic brain. J. Exp. Biol. 2004, 207, 3221-3231.
20. Zalba, G.; Fortuno, A.; San Jose, G.; Moreno, M.U.; Beloqui, O.; Diez, J. Oxidative stress, endothelial dysfunction and cerebrovascular disease. Cerebrovasc. Dis. 2007, 24, 24-29.
21. Berry, C.E.; Hare, J.M. Xanthine oxidoreductase and cardiovascular disease: Molecular mechanisms and pathophysiological implications. J. Physiol. 2004, 555, 589-606.
22. Paravicini, T.M.; Sobey, C.G. Cerebral vascular effects of reactive oxygen species: Recent evidence for a role of NAD(P)H-oxidase. Clin. Exp. Pharmacol. Physiol. 2003, 30, 855-859.
23. Im, J.Y.; Kim, D.; Paik, S.G.; Han, P.L. Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation. Free Radic. Biol. Med. 2006, 41, 960-972.
24. Fleming, I.; Michaelis, U.R.; Bredenkotter, D.; Fisslthaler, B.; Dehghani, F.; Brandes, R.P.; Busse, R. Endothelium-derived hyperpolarizing factor synthase (cytochrome p450 2c9) is a functionally significant source of reactive oxygen species in coronary arteries. Circ. Res. 2001, 88, 44-51.
25. Abramov, A.Y.; Scorziello, A.; Duchen, M.R. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J. Neurosci. 2007, 27, 1129-1138.
26. Beske, P.H.; Jackson, D.A. NADPH oxidase mediates the oxygen-glucose deprivation/ reperfusion-induced increase in the tyrosine phosphorylation of the n-methyl-D-aspartate receptor NR2A subunit in retinoic acid differentiated SH-SY5Y cells. J. Mol. Signal. 2012, 7, 15.
27. Suh, S.W.; Shin, B.S.; Ma, H.; van Hoecke, M.; Brennan, A.M.; Yenari, M.A.; Swanson, R.A. Glucose and NAD(P)H oxidase drive neuronal superoxide formation in stroke. Ann. Neurol. 2008, 64, 654-663.
28. Durukan, A.; Tatlisumak, T. Acute ischemic stroke: Overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol. Biochem. Behav. 2007, 87, 179-197.
29. Manea, A. NADPH oxidase-derived reactive oxygen species: Involvement in vascular physiology and pathology. Cell Tissue Res. 2010, 342, 325-339.
30. Mills, E.; Dong, X.P.; Wang, F.; Xu, H. Mechanisms of brain iron transport: Insight into neurodegeneration and cns disorders. Future Med. Chem. 2010, 2, 51-64.
31. Reiter, R.J. Oxidative processes and antioxidative defense mechanisms in the aging brain. FASEB J. 1995, 9, 526-533.
32. Liu, J.; Yeo, H.C.; Overvik-Douki, E.; Hagen, T.; Doniger, S.J.; Chyu, D.W.; Brooks, G.A.; Ames, B.N. Chronically and acutely exercised rats: Biomarkers of oxidative stress and endogenous antioxidants. J. Appl. Physiol. 2000, 89, 21-28.
33. Matsuo, M.; Gomi, F.; Dooley, M.M. Age-related alterations in antioxidant capacity and lipid peroxidation in brain, liver, and lung homogenates of normal and vitamin E-deficient rats. Mech. Ageing Dev. 1992, 64, 273-292.
34. Chan, P.H. Reactive oxygen radicals in signaling and damage in the ischemic brain. J. Cereb. Blood Flow Metab. 2001, 21, 2-14.
35. Kamii, H.; Mikawa, S.; Murakami, K.; Kinouchi, H.; Yoshimoto, T.; Reola, L.; Carlson, E.; Epstein, C.J.; Chan, P.H. Effects of nitric oxide synthase inhibition on brain infarction in sod-1-transgenic mice following transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 1996, 16, 1153-1157.
36. Keller, J.N.; Kindy, M.S.; Holtsberg, F.W.; St Clair, D.K.; Yen, H.C.; Germeyer, A.; Steiner, S.M.; Bruce-Keller, A.J.; Hutchins, J.B.; Mattson, M.P. Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: Suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J. Neurosci. 1998, 18, 687-697.
37. Sheng, H.; Bart, R.D.; Oury, T.D.; Pearlstein, R.D.; Crapo, J.D.; Warner, D.S. Mice overexpressing extracellular superoxide dismutase have increased resistance to focal cerebral ischemia. Neuroscience 1999, 88, 185-191.
38. Yang, G.; Chan, P.H.; Chen, J.; Carlson, E.; Chen, S.F.; Weinstein, P.; Epstein, C.J.; Kamii, H. Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia. Stroke 1994, 25, 165-170.
39. Murakami, K.; Kondo, T.; Epstein, C.J.; Chan, P.H. Overexpression of CuZn-superoxide dismutase reduces hippocampal injury after global ischemia in transgenic mice. Stroke 1997, 28, 1797-1804.
40. Kondo, T.; Reaume, A.G.; Huang, T.T.; Carlson, E.; Murakami, K.; Chen, S.F.; Hoffman, E.K.; Scott, R.W.; Epstein, C.J.; Chan, P.H. Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J. Neurosci. 1997, 17, 4180-4189.
41. Murakami, K.; Kondo, T.; Kawase, M.; Li, Y.; Sato, S.; Chen, S.F.; Chan, P.H. Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J. Neurosci. 1998, 18, 205-213.
42. Sheng, H.; Brady, T.C.; Pearlstein, R.D.; Crapo, J.D.; Warner, D.S. Extracellular superoxide dismutase deficiency worsens outcome from focal cerebral ischemia in the mouse. Neurosci. Lett. 1999, 267, 13-16.
43. Crack, P.J.; Taylor, J.M.; Flentjar, N.J.; de Haan, J.; Hertzog, P.; Iannello, R.C.; Kola, I. Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (Gpx-1) knockout mouse brain in response to ischemia/reperfusion injury. J. Neurochem. 2001, 78, 1389-1399.
44. Weisbrot-Lefkowitz, M.; Reuhl, K.; Perry, B.; Chan, P.H.; Inouye, M.; Mirochnitchenko, O. Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage. Brain Res. Mol. Brain Res. 1998, 53, 333-338.
45. Crack, P.J.; Taylor, J.M.; de Haan, J.B.; Kola, I.; Hertzog, P.; Iannello, R.C. Glutathione peroxidase-1 contributes to the neuroprotection seen in the superoxide dismutase-1 transgenic mouse in response to ischemia/reperfusion injury. J. Cereb. Blood Flow Metab. 2003, 23, 19-22.
46. De Haan, J.B.; Crack, P.J.; Flentjar, N.; Iannello, R.C.; Hertzog, P.J.; Kola, I. An imbalance in antioxidant defense affects cellular function: The pathophysiological consequences of a reduction in antioxidant defense in the glutathione peroxidase-1 (Gpx1) knockout mouse. Redox. Rep. 2003, 8, 69-79.
47. Baker, K.; Marcus, C.B.; Huffman, K.; Kruk, H.; Malfroy, B.; Doctrow, S.R. Synthetic combined superoxide dismutase/catalase mimetics are protective as a delayed treatment in a rat stroke model: A key role for reactive oxygen species in ischemic brain injury. J. Pharmacol. Exp. Ther. 1998, 284, 215-221.
48. Chaudhary, G.; Sinha, K.; Gupta, Y.K. Protective effect of exogenous administration of alpha-tocopherol in middle cerebral artery occlusion model of cerebral ischemia in rats. Fundam. Clin. Pharmacol. 2003, 17, 703-707.
49. Henry, P.T.; Chandy, M.J. Effect of ascorbic acid on infarct size in experimental focal cerebral ischaemia and reperfusion in a primate model. Acta Neurochir. (Wien) 1998, 140, 977-980.
50. Lagowska-Lenard, M.; Stelmasiak, Z.; Bartosik-Psujek, H. Influence of vitamin C on markers of oxidative stress in the earliest period of ischemic stroke. Pharmacol. Rep. 2010, 62, 751-756.
51. Ullegaddi, R.; Powers, H.J.; Gariballa, S.E. Antioxidant supplementation enhances antioxidant capacity and mitigates oxidative damage following acute ischaemic stroke. Eur. J. Clin. Nutr. 2005, 59, 1367-1373.
52. Amaro, S.; Chamorro, A. Translational stroke research of the combination of thrombolysis and antioxidant therapy. Stroke 2011, 42, 1495-1499.
53. Margaill, I.; Plotkine, M.; Lerouet, D. Antioxidant strategies in the treatment of stroke. Free Radic. Biol. Med. 2005, 39, 429-443.
54. Fisher, M.; Feuerstein, G.; Howells, D.W.; Hurn, P.D.; Kent, T.A.; Savitz, S.I.; Lo, E.H. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 2009, 40, 2244-2250.
55. Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999, 30, 2752-2758.
56. Bath, P.M.; Gray, L.J.; Bath, A.J.; Buchan, A.; Miyata, T.; Green, A.R. Effects of NXY-059 in experimental stroke: An individual animal meta-analysis. Br. J. Pharmacol. 2009, 157, 1157-1171.
57. Nakase, T.; Yoshioka, S.; Suzuki, A. Free radical scavenger, edaravone, reduces the lesion size of lacunar infarction in human brain ischemic stroke. BMC Neurol. 2011, 11, 39.
58. Lapchak, P.A. A critical assessment of edaravone acute ischemic stroke efficacy trials: Is edaravone an effective neuroprotective therapy? Expert Opin. Pharmacother. 2010, 11, 1753-1763.
59. Lapchak, P.A.; Zivin, J.A. The lipophilic multifunctional antioxidant edaravone (radicut) improves behavior following embolic strokes in rabbits: A combination therapy study with tissue plasminogen activator. Exp. Neurol. 2009, 215, 95-100.
60. Isahaya, K.; Yamada, K.; Yamatoku, M.; Sakurai, K.; Takaishi, S.; Kato, B.; Hirayama, T.; Hasegawa, Y. Effects of edaravone, a free radical scavenger, on serum levels of inflammatory biomarkers in acute brain infarction. J. Stroke Cerebrovasc. Dis. 2012, 21, 102-107.
61. Roulston, C.L.; McCann, S.; Weston, R.M.; Jarrott, B. Animal Models of Stroke for Preclinical Drug Development: A Comparative Study of Flavonols for Cytoprotection. In Translational Stroke Research; Springer: New York, NY, USA, 2012; pp. 493-524.
62. Halliwell, B. Free radicals, antioxidants, and human disease: Curiosity, cause, or consequence? Lancet 1994, 344, 721-724.
63. Rimm, E.B.; Katan, M.B.; Ascherio, A.; Stampfer, M.J.; Willett, W.C. Relation between intake of flavonoids and risk for coronary heart disease in male health professionals. Ann. Intern. Med. 1996, 125, 384-389.
64. Rivera, F.; Urbanavicius, J.; Gervaz, E.; Morquio, A.; Dajas, F. Some aspects of the in vivo neuroprotective capacity of flavonoids: Bioavailability and structure-activity relationship. Neurotox. Res. 2004, 6, 543-553.
65. Roulston, C.L.; Callaway, J.K.; Jarrott, B.; Woodman, O.L.; Dusting, G.J. Using behaviour to predict stroke severity in conscious rats: Post-stroke treatment with 3',4'-dihydroxyflavonol improves recovery. Eur. J. Pharmacol. 2008, 584, 100-110.
66. Firuzi, O.; Miri, R.; Tavakkoli, M.; Saso, L. Antioxidant therapy: Current status and future prospects. Curr. Med. Chem. 2011, 18, 3871-3888.
67. Kamat, C.D.; Gadal, S.; Mhatre, M.; Williamson, K.S.; Pye, Q.N.; Hensley, K. Antioxidants in central nervous system diseases: Preclinical promise and translational challenges. J. Alzheimers Dis. 2008, 15, 473-493.
68. Andriantsitohaina, R.; Duluc, L.; Garcia-Rodriguez, J.C.; Gil-del Valle, L.; Guevara-Garcia, M.; Simard, G.; Soleti, R.; Su, D.F.; Velasquez-Perez, L.; Wilson, J.X.; Laher, I. Systems biology of antioxidants. Clin. Sci. (Lond.) 2012, 123, 173-192.
69. Pandya, R.S.; Mao, L.; Zhou, H.; Zhou, S.; Zeng, J.; Popp, A.J.; Wang, X. Central nervous system agents for ischemic stroke: Neuroprotection mechanisms. Cent. Nerv. Syst. Agents Med. Chem. 2011, 11, 81-97.
70. Slemmer, J.E.; Shacka, J.J.; Sweeney, M.I.; Weber, J.T. Antioxidants and free radical scavengers for the treatment of stroke, traumatic brain injury and aging. Curr. Med. Chem. 2008, 15, 404-414.
71. Cherubini, A.; Ruggiero, C.; Morand, C.; Lattanzio, F.; Dell'aquila, G.; Zuliani, G.; Di Iorio, A.; Andres-Lacueva, C. Dietary antioxidants as potential pharmacological agents for ischemic stroke. Curr. Med. Chem. 2008, 15, 1236-1248.
72. Wang, C.X.; Shuaib, A. Neuroprotective effects of free radical scavengers in stroke. Drugs Aging 2007, 24, 537-546.
73. Doeppner, T.R.; Hermann, D.M. Free radical scavengers and spin traps-Therapeutic implications for ischemic stroke. Best Pract. Res. Clin. Anaesthesiol. 2010, 24, 511-520.
74. Kunz, A.; Anrather, J.; Zhou, P.; Orio, M.; Iadecola, C. Cyclooxygenase-2 does not contribute to postischemic production of reactive oxygen species. J. Cereb. Blood Flow Metab. 2007, 27, 545-551.
75. Brown, D.I.; Griendling, K.K. Nox proteins in signal transduction. Free Radic. Biol. Med. 2009, 47, 1239-1253.
76. Infanger, D.W.; Sharma, R.V.; Davisson, R.L. NADPH oxidases of the brain: Distribution, regulation, and function. Antioxid. Redox Signal. 2006, 8, 1583-1596.
77. Sorce, S.; Krause, K.H. Nox enzymes in the central nervous system: From signaling to disease. Antioxid. Redox Signal. 2009, 11, 2481-2504.
78. Lambeth, J.D.; Krause, K.H.; Clark, R.A. Nox enzymes as novel targets for drug development. Semin. Immunopathol. 2008, 30, 339-363.
79. Baldridge, C.W.; Gerard, R.W. The extra respiration of phagocytosis. Am. J. Physiol. 1933, 103, 235-236.
80. Baehner, R.L.; Nathan, D.G. Leukocyte oxidase: Defective activity in chronic granulomatous disease. Science 1967, 155, 835-836.
81. Berendes, H.; Bridges, R.A.; Good, R.A. A fatal granulomatosus of childhood: The clinical study of a new syndrome. Minn. Med. 1957, 40, 309-312.
82. Landing, B.H.; Shirkey, H.S. A syndrome of recurrent infection and infiltration of viscera by pigmented lipid histiocytes. Pediatrics 1957, 20, 431-438.
83. Babior, B.M.; Kipnes, R.S.; Curnutte, J.T. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J. Clin. Invest. 1973, 52, 741-744.
84. Curnutte, J.T.; Whitten, D.M.; Babior, B.M. Defective superoxide production by granulocytes from patients with chronic granulomatous disease. N. Engl. J. Med. 1974, 290, 593-597.
85. Hohn, D.C.; Lehrer, R.I. NADPH oxidase deficiency in X-linked chronic granulomatous disease. J. Clin. Invest. 1975, 55, 707-713.
86. Curnutte, J.T. Chronic granulomatous disease: The solving of a clinical riddle at the molecular level. Clin. Immunol. Immunopathol. 1993, 67, S2-S15.
87. Babior, B.M.; Lambeth, J.D.; Nauseef, W. The neutrophil NAD(P)H oxidase. Arch. Biochem. Biophys. 2002, 397, 342-344.
88. Vignais, P.V. The superoxide-generating NAD(P)H oxidase: Structural aspects and activation mechanism. Cell. Mol. Life Sci. 2002, 59, 1428-1459.
89. Nauseef, W.M. Biological roles for the nox family NAD(P)H oxidases. J. Biol. Chem. 2008, 283, 16961-16965.
90. Rada, B.; Leto, T.L. Oxidative innate immune defenses by Nox/Duox family NAD(P)H oxidases. Contrib. Microbiol. 2008, 15, 164-187.
91. Gorlach, A.; Holtermann, G.; Jelkmann, W.; Hancock, J.T.; Jones, S.A.; Jones, O.T.; Acker, H. Photometric characteristics of haem proteins in erythropoietin-producing hepatoma cells (HepG2). Biochem. J. 1993, 290, 771-776.
92. Meier, B.; Radeke, H.H.; Selle, S.; Younes, M.; Sies, H.; Resch, K.; Habermehl, G.G. Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumour necrosis factor-alpha. Biochem. J. 1989, 263, 539-545.
93. Suh, Y.A.; Arnold, R.S.; Lassegue, B.; Shi, J.; Xu, X.; Sorescu, D.; Chung, A.B.; Griendling, K.K.; Lambeth, J.D. Cell transformation by the superoxide-generating oxidase Mox1. Nature 1999, 401, 79-82.
94. Kikuchi, H.; Hikage, M.; Miyashita, H.; Fukumoto, M. NADPH oxidase subunit, gp91(phox) homologue, preferentially expressed in human colon epithelial cells. Gene 2000, 254, 237-243.
95. Banfi, B.; Malgrange, B.; Knisz, J.; Steger, K.; Dubois-Dauphin, M.; Krause, K.H. Nox3, a superoxide-generating NAD(P)H oxidase of the inner ear. J. Biol. Chem. 2004, 279, 46065-46072.
96. Geiszt, M.; Kopp, J.B.; Varnai, P.; Leto, T.L. Identification of renox, an NAD(P)H oxidase in kidney. Proc. Natl. Acad. Sci. USA 2000, 97, 8010-8014.
97. Lassegue, B.; Griendling, K.K. NADPH oxidases: Functions and pathologies in the vasculature. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 653-661.
98. 2+-activated NAD(P)H oxidase in testis, spleen, and lymph nodes. J. Biol. Chem. 2001, 276, 37594-37601.
99. De Deken, X.; Wang, D.; Many, M.C.; Costagliola, S.; Libert, F.; Vassart, G.; Dumont, J.E.; Miot, F. Cloning of two human thyroid cdnas encoding new members of the NAD(P)H oxidase family. J. Biol. Chem. 2000, 275, 23227-23233.
100. Dupuy, C.; Ohayon, R.; Valent, A.; Noel-Hudson, M.S.; Deme, D.; Virion, A. Purification of a novel flavoprotein involved in the thyroid NAD(P)H oxidase. Cloning of the porcine and human cdnas. J. Biol. Chem. 1999, 274, 37265-37269.
101. Edens, W.A.; Sharling, L.; Cheng, G.; Shapira, R.; Kinkade, J.M.; Lee, T.; Edens, H.A.; Tang, X.; Sullards, C.; Flaherty, D.B.; et al. Tyrosine cross-linking of extracellular matrix is catalyzed by Duox, a multidomain oxidase/peroxidase with homology to the phagocyte oxidase subunit gp91phox. J. Cell Biol. 2001, 154, 879-891.
102. Kawahara, T.; Ritsick, D.; Cheng, G.; Lambeth, J.D. Point mutations in the proline-rich region of p22phox are dominant inhibitors of Nox1-and Nox2-dependent reactive oxygen generation. J. Biol. Chem. 2005, 280, 31859-31869.
103. Selemidis, S.; Sobey, C.G.; Wingler, K.; Schmidt, H.H.; Drummond, G.R. NADPH oxidases in the vasculature: Molecular features, roles in disease and pharmacological inhibition. Pharmacol. Ther. 2008, 120, 254-291.
104. Cheng, G.; Ritsick, D.; Lambeth, J.D. Nox3 regulation by NOXO1, p47phox, and p67phox. J. Biol. Chem. 2004, 279, 34250-34255.
105. Lambeth, J.D.; Kawahara, T.; Diebold, B. Regulation of Nox and Duox enzymatic activity and expression. Free Radic. Biol. Med. 2007, 43, 319-331.
106. Ueno, N.; Takeya, R.; Miyano, K.; Kikuchi, H.; Sumimoto, H. The NAD(P)H oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: Its regulation by oxidase organizers and activators. J. Biol. Chem. 2005, 280, 23328-23339.
107. Lyle, A.N.; Deshpande, N.N.; Taniyama, Y.; Seidel-Rogol, B.; Pounkova, L.; Du, P.; Papaharalambus, C.; Lassegue, B.; Griendling, K.K. Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ. Res. 2009, 105, 249-259.
108. Martyn, K.D.; Frederick, L.M.; von Loehneysen, K.; Dinauer, M.C.; Knaus, U.G. Functional analysis of Nox4 reveals unique characteristics compared to other NAD(P)H oxidases. Cell. Signal. 2006, 18, 69-82.
109. Sumimoto, H. Structure, regulation and evolution of Nox-family NAD(P)H oxidases that produce reactive oxygen species. FEBS J. 2008, 275, 3249-3277.
110. Cheng, G.; Lambeth, J.D. NOXO1, regulation of lipid binding, localization, and activation of Nox1 by the Phox homology (PX) domain. J. Biol. Chem. 2004, 279, 4737-4742.
111. Lam, G.Y.; Huang, J.; Brumell, J.H. The many roles of Nox2 NAD(P)H oxidase-derived ROS in immunity. Semin. Immunopathol. 2010, 32, 415-430.
112. Lambeth, J.D. Nox enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 2004, 4, 181-189.
113. Touyz, R.M. Reactive oxygen species in vascular biology: Role in arterial hypertension. Expert Rev. Cardiovasc. Ther. 2003, 1, 91-106.
114. Dale, D.C.; Boxer, L.; Liles, W.C. The phagocytes: Neutrophils and monocytes. Blood 2008, 112, 935-945.
115. Reinehr, R.; Gorg, B.; Becker, S.; Qvartskhava, N.; Bidmon, H.J.; Selbach, O.; Haas, H.L.; Schliess, F.; Haussinger, D. Hypoosmotic swelling and ammonia increase oxidative stress by NAD(P)H oxidase in cultured astrocytes and vital brain slices. Glia 2007, 55, 758-771.
116. Mizuki, K.; Kadomatsu, K.; Hata, K.; Ito, T.; Fan, Q.W.; Kage, Y.; Fukumaki, Y.; Sakaki, Y.; Takeshige, K.; Sumimoto, H. Functional modules and expression of mouse p40(phox) and p67(phox), SH3-domain-containing proteins involved in the phagocyte NAD(P)H oxidase complex. Eur. J. Biochem. 1998, 251, 573-582.
117. Dvorakova, M.; Hohler, B.; Richter, E.; Burritt, J.B.; Kummer, W. Rat sensory neurons contain cytochrome b558 large subunit immunoreactivity. Neuroreport 1999, 10, 2615-2617.
118. Tammariello, S.P.; Quinn, M.T.; Estus, S. NADPH oxidase contributes directly to oxidative stress and apoptosis in nerve growth factor-deprived sympathetic neurons. J. Neurosci. 2000, 20, RC53.
119. Noh, K.M.; Koh, J.Y. Induction and activation by zinc of NAD(P)H oxidase in cultured cortical neurons and astrocytes. J. Neurosci. 2000, 20, RC111.
120. Park, K.W.; Jin, B.K. Thrombin-induced oxidative stress contributes to the death of hippocampal neurons: Role of neuronal NAD(P)H oxidase. J. Neurosci. Res. 2008, 86, 1053-1063.
121. Tejada-Simon, M.V.; Serrano, F.; Villasana, L.E.; Kanterewicz, B.I.; Wu, G.Y.; Quinn, M.T.; Klann, E. Synaptic localization of a functional NAD(P)H oxidase in the mouse hippocampus. Mol. Cell. Neurosci. 2005, 29, 97-106.
122. Kim, M.J.; Shin, K.S.; Chung, Y.B.; Jung, K.W.; Cha, C.I.; Shin, D.H. Immunohistochemical study of p47phox and gp91phox distributions in rat brain. Brain Res. 2005, 1040, 178-186.
123. Serrano, F.; Kolluri, N.S.; Wientjes, F.B.; Card, J.P.; Klann, E. NADPH oxidase immunoreactivity in the mouse brain. Brain Res. 2003, 988, 193-198.
124. Green, S.P.; Cairns, B.; Rae, J.; Errett-Baroncini, C.; Hongo, J.A.; Erickson, R.W.; Curnutte, J.T. Induction of gp91-phox, a component of the phagocyte NAD(P)H oxidase, in microglial cells during central nervous system inflammation. J. Cereb. Blood Flow Metab. 2001, 21, 374-384.
125. Ha, J.S.; Lee, J.E.; Lee, J.R.; Lee, C.S.; Maeng, J.S.; Bae, Y.S.; Kwon, K.S.; Park, S.S. Nox4-dependent H2O2 production contributes to chronic glutamate toxicity in primary cortical neurons. Exp. Cell. Res. 2010, 316, 1651-1661.
126. Kahles, T.; Kohnen, A.; Heumueller, S.; Rappert, A.; Bechmann, I.; Liebner, S.; Wittko, I.M.; Neumann-Haefelin, T.; Steinmetz, H.; Schroeder, K.; et al. NADPH oxidase Nox1 contributes to ischemic injury in experimental stroke in mice. Neurobiol. Dis. 2010, 40, 185-192.
127. Ibi, M.; Katsuyama, M.; Fan, C.; Iwata, K.; Nishinaka, T.; Yokoyama, T.; Yabe-Nishimura, C. Nox1/NAD(P)H oxidase negatively regulates nerve growth factor-induced neurite outgrowth. Free Radic. Biol. Med. 2006, 40, 1785-1795.
128. Suzukawa, K.; Miura, K.; Mitsushita, J.; Resau, J.; Hirose, K.; Crystal, R.; Kamata, T. Nerve growth factor-induced neuronal differentiation requires generation of Rac1-regulated reactive oxygen species. J. Biol. Chem. 2000, 275, 13175-13178.
129. Liu, Q.; Kang, J.H.; Zheng, R.L. NADPH oxidase produces reactive oxygen species and maintains survival of rat astrocytes. Cell Biochem. Funct. 2005, 23, 93-100.
130. Abramov, A.Y.; Jacobson, J.; Wientjes, F.; Hothersall, J.; Canevari, L.; Duchen, M.R. Expression and modulation of an NAD(P)H oxidase in mammalian astrocytes. J. Neurosci. 2005, 25, 9176-9184.
131. Block, M.L.; Zecca, L.; Hong, J.S. Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nat. Rev. Neurosci. 2007, 8, 57-69.
132. Sankarapandi, S.; Zweier, J.L.; Mukherjee, G.; Quinn, M.T.; Huso, D.L. Measurement and characterization of superoxide generation in microglial cells: Evidence for an NAD(P)H oxidase-dependent pathway. Arch. Biochem. Biophys. 1998, 353, 312-321.
133. Choi, S.H.; Lee, D.Y.; Kim, S.U.; Jin, B.K. Thrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo: Role of microglial NAD(P)H oxidase. J. Neurosci. 2005, 25, 4082-4090.
134. Lavigne, M.C.; Malech, H.L.; Holland, S.M.; Leto, T.L. Genetic requirement of p47phox for superoxide production by murine microglia. FASEB J. 2001, 15, 285-287.
135. Li, B.; Bedard, K.; Sorce, S.; Hinz, B.; Dubois-Dauphin, M.; Krause, K.H. Nox4 expression in human microglia leads to constitutive generation of reactive oxygen species and to constitutive IL-6 expression. J. Innate Immun. 2009, 1, 570-581.
136. Cheret, C.; Gervais, A.; Lelli, A.; Colin, C.; Amar, L.; Ravassard, P.; Mallet, J.; Cumano, A.; Krause, K.H.; Mallat, M. Neurotoxic activation of microglia is promoted by a Nox1-dependent NAD(P)H oxidase. J. Neurosci. 2008, 28, 12039-12051.
137. Harrigan, T.J.; Abdullaev, I.F.; Jourd'heuil, D.; Mongin, A.A. Activation of microglia with zymosan promotes excitatory amino acid release via volume-regulated anion channels: The role of NAD(P)H oxidases. J. Neurochem. 2008, 106, 2449-2462.
138. Mander, P.K.; Jekabsone, A.; Brown, G.C. Microglia proliferation is regulated by hydrogen peroxide from NAD(P)H oxidase. J. Immunol. 2006, 176, 1046-1052.
139. Miller, A.A.; Budzyn, K.; Sobey, C.G. Vascular dysfunction in cerebrovascular disease: Mechanisms and therapeutic intervention. Clin. Sci. (Lond.) 2010, 119, 1-17.
140. Chrissobolis, S.; Faraci, F.M. The role of oxidative stress and NAD(P)H oxidase in cerebrovascular disease. Trends Mol. Med. 2008, 14, 495-502.
141. Miller, A.A.; Drummond, G.R.; de Silva, T.M.; Mast, A.E.; Hickey, H.; Williams, J.P.; Broughton, B.R.; Sobey, C.G. NADPH oxidase activity is higher in cerebral versus systemic arteries of four animal species: Role of Nox2. Am. J. Physiol. Heart Circ. Physiol. 2009, 296, H220-H225.
142. Miller, A.A.; Drummond, G.R.; Schmidt, H.H.; Sobey, C.G. NADPH oxidase activity and function are profoundly greater in cerebral versus systemic arteries. Circ. Res. 2005, 97, 1055-1062.
143. Ago, T.; Kitazono, T.; Kuroda, J.; Kumai, Y.; Kamouchi, M.; Ooboshi, H.; Wakisaka, M.; Kawahara, T.; Rokutan, K.; Ibayashi, S.; et al. NAD(P)H oxidases in rat basilar arterial endothelial cells. Stroke 2005, 36, 1040-1046.
144. Jackman, K.A.; Miller, A.A.; Drummond, G.R.; Sobey, C.G. Importance of NOX1 for angiotensin II-induced cerebrovascular superoxide production and cortical infarct volume following ischemic stroke. Brain Res. 2009, 1286, 215-220.
145. Cheng, G.; Cao, Z.; Xu, X.; van Meir, E.G.; Lambeth, J.D. Homologs of gp91phox: Cloning and tissue expression of Nox3, Nox4, and Nox5. Gene 2001, 269, 131-140.
146. Paravicini, T.M.; Chrissobolis, S.; Drummond, G.R.; Sobey, C.G. Increased NAD(P)H-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NAD(P)H in vivo. Stroke 2004, 35, 584-589.
147. Park, L.; Anrather, J.; Zhou, P.; Frys, K.; Wang, G.; Iadecola, C. Exogenous NAD(P)H increases cerebral blood flow through NAD(P)H oxidase-dependent and-independent mechanisms. Arterioscler. Thromb. Vasc. Biol. 2004, 24, 1860-1865.
148. Kim, J.S.; Yeo, S.; Shin, D.G.; Bae, Y.S.; Lee, J.J.; Chin, B.R.; Lee, C.H.; Baek, S.H. Glycogen synthase kinase 3beta and beta-catenin pathway is involved in toll-like receptor 4-mediated NAD(P)H oxidase 1 expression in macrophages. FEBS J. 2010, 277, 2830-2837.
149. Sorescu, D.; Weiss, D.; Lassegue, B.; Clempus, R.E.; Szocs, K.; Sorescu, G.P.; Valppu, L.; Quinn, M.T.; Lambeth, J.D.; Vega, J.D.; et al. Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 2002, 105, 1429-1435.
150. Lee, C.F.; Qiao, M.; Schroder, K.; Zhao, Q.; Asmis, R. Nox4 is a novel inducible source of reactive oxygen species in monocytes and macrophages and mediates oxidized low density lipoprotein-induced macrophage death. Circ. Res. 2010, 106, 1489-1497.
151. Hong, H.; Zeng, J.S.; Kreulen, D.L.; Kaufman, D.I.; Chen, A.F. Atorvastatin protects against cerebral infarction via inhibition of NAD(P)H oxidase-derived superoxide in ischemic stroke. Am. J. Physiol. Heart Circ. Physiol. 2006, 291, H2210-H2215.
152. Lu, Q.; Xia, N.; Xu, H.; Guo, L.; Wenzel, P.; Daiber, A.; Munzel, T.; Forstermann, U.; Li, H. Betulinic acid protects against cerebral ischemia-reperfusion injury in mice by reducing oxidative and nitrosative stress. Nitric Oxide 2011, 24, 132-138.
153. Murotomi, K.; Takagi, N.; Takeo, S.; Tanonaka, K. NADPH oxidase-mediated oxidative damage to proteins in the postsynaptic density after transient cerebral ischemia and reperfusion. Mol. Cell. Neurosci. 2011, 46, 681-688.
154. Jackman, K.A.; Miller, A.A.; de Silva, T.M.; Crack, P.J.; Drummond, G.R.; Sobey, C.G. Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice. Br. J. Pharmacol. 2009, 156, 680-688.
155. Walder, C.E.; Green, S.P.; Darbonne, W.C.; Mathias, J.; Rae, J.; Dinauer, M.C.; Curnutte, J.T.; Thomas, G.R. Ischemic stroke injury is reduced in mice lacking a functional NAD(P)H oxidase. Stroke 1997, 28, 2252-2258.
156. Schroeter, M.; Jander, S.; Witte, O.W.; Stoll, G. Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion. J. Neuroimmunol. 1994, 55, 195-203.
157. Gelderblom, M.; Leypoldt, F.; Lewerenz, J.; Birkenmayer, G.; Orozco, D.; Ludewig, P.; Thundyil, J.; Arumugam, T.V.; Gerloff, C.; Tolosa, E.; et al. The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice. J. Cereb. Blood Flow Metab. 2012, 32, 835-843.
158. Brait, V.H.; Jackman, K.A.; Walduck, A.K.; Selemidis, S.; Diep, H.; Mast, A.E.; Guida, E.; Broughton, B.R.; Drummond, G.R.; Sobey, C.G. Mechanisms contributing to cerebral infarct size after stroke: Gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J. Cereb. Blood Flow Metab. 2010, 30, 1306-1317.
159. Weston, R.M.; Jarrott, B.; Ishizuka, Y.; Callaway, J.K. AM-36 modulates the neutrophil inflammatory response and reduces breakdown of the blood brain barrier after endothelin-1 induced focal brain ischaemia. Br. J. Pharmacol. 2006, 149, 712-723.
160. Tang, X.N.; Zheng, Z.; Giffard, R.G.; Yenari, M.A. Significance of marrow-derived nicotinamide adenine dinucleotide phosphate oxidase in experimental ischemic stroke. Ann. Neurol. 2011, 70, 606-615.
161. Jackson, S.H.; Devadas, S.; Kwon, J.; Pinto, L.A.; Williams, M.S. T cells express a phagocyte-type NAD(P)H oxidase that is activated after T cell receptor stimulation. Nat. Immunol. 2004, 5, 818-827.
162. Coimbra, C.; Drake, M.; Boris-Moller, F.; Wieloch, T. Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalopathic processes following ischemia. Stroke 1996, 27, 1578-1585.
163. Fox, C.; Dingman, A.; Derugin, N.; Wendland, M.F.; Manabat, C.; Ji, S.; Ferriero, D.M.; Vexler, Z.S. Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion. J. Cereb. Blood Flow Metab. 2005, 25, 1138-1149.
164. Valtysson, J.; Hillered, L.; Andine, P.; Hagberg, H.; Persson, L. Neuropathological endpoints in experimental stroke pharmacotherapy: The importance of both early and late evaluation. Acta Neurochir. (Wien) 1994, 129, 58-63.
165. Kahles, T.; Luedike, P.; Endres, M.; Galla, H.J.; Steinmetz, H.; Busse, R.; Neumann-Haefelin, T.; Brandes, R.P. NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 2007, 38, 3000-3006.
166. Chen, H.; Kim, G.S.; Okami, N.; Narasimhan, P.; Chan, P.H. NADPH oxidase is involved in post-ischemic brain inflammation. Neurobiol. Dis. 2011, 42, 341-348.
167. Chen, H.; Song, Y.S.; Chan, P.H. Inhibition of NAD(P)H oxidase is neuroprotective after ischemia-reperfusion. J. Cereb. Blood Flow Metab. 2009, 29, 1262-1272.
168. Kim, H.A.; Brait, V.H.; Lee, S.; de Silva, T.M.; Diep, H.; Eisenhardt, A.; Drummond, G.R.; Sobey, C.G. Brain infarct volume after permanent focal ischemia is not dependent on Nox2 expression. Brain Res. 2012, 1483, 105-111.
169. Hur, J.; Lee, P.; Kim, M.J.; Kim, Y.; Cho, Y.W. Ischemia-activated microglia induces neuronal injury via activation of gp91phox NAD(P)H oxidase. Biochem. Biophys. Res. Commun. 2010, 391, 1526-1530.
170. Spranger, M.; Kiprianova, I.; Krempien, S.; Schwab, S. Reoxygenation increases the release of reactive oxygen intermediates in murine microglia. J. Cereb. Blood Flow Metab. 1998, 18, 670-674.
171. Mander, P.; Brown, G.C. Activation of microglial NAD(P)H oxidase is synergistic with glial iNOS expression in inducing neuronal death: A dual-key mechanism of inflammatory neurodegeneration. J. Neuroinflammation 2005, 2, 20.
172. Knorpp, T.; Robinson, S.R.; Crack, P.J.; Dringen, R. Glutathione peroxidase-1 contributes to the protection of glutamine synthetase in astrocytes during oxidative stress. J. Neural. Transm. 2006, 113, 1145-1155.
173. Abramov, A.Y.; Duchen, M.R. The role of an astrocytic NAD(P)H oxidase in the neurotoxicity of amyloid beta peptides. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2005, 360, 2309-2314.
174. Desagher, S.; Glowinski, J.; Premont, J. Astrocytes protect neurons from hydrogen peroxide toxicity. J. Neurosci. 1996, 16, 2553-2562.
175. Rosenberg, P.A.; Aizenman, E. Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci. Lett. 1989, 103, 162-168.
176. Tang, L.L.; Ye, K.; Yang, X.F.; Zheng, J.S. Apocynin attenuates cerebral infarction after transient focal ischaemia in rats. J. Int. Med. Res. 2007, 35, 517-522.
177. Tang, X.N.; Cairns, B.; Cairns, N.; Yenari, M.A. Apocynin improves outcome in experimental stroke with a narrow dose range. Neuroscience 2008, 154, 556-562.
178. Genovese, T.; Mazzon, E.; Paterniti, I.; Esposito, E.; Bramanti, P.; Cuzzocrea, S. Modulation of NAD(P)H oxidase activation in cerebral ischemia/reperfusion injury in rats. Brain Res. 2011, 1372, 92-102.
179. Kelly, K.A.; Li, X.; Tan, Z.; vanGilder, R.L.; Rosen, C.L.; Huber, J.D. NOX2 inhibition with apocynin worsens stroke outcome in aged rats. Brain Res. 2009, 1292, 165-172.
180. Doverhag, C.; Keller, M.; Karlsson, A.; Hedtjarn, M.; Nilsson, U.; Kapeller, E.; Sarkozy, G.; Klimaschewski, L.; Humpel, C.; Hagberg, H.; et al. Pharmacological and genetic inhibition of NAD(P)H oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice. Neurobiol. Dis. 2008, 31, 133-144.
181. Arimura, K.; Ago, T.; Kuroda, J.; Ishitsuka, K.; Nishimura, A.; Sugimori, H.; Kamouchi, M.; Sasaki, T.; Kitazono, T. Role of NAD(P)H oxidase 4 in brain endothelial cells after ischemic stroke. Stroke 2012, 43, A2514.
182. De Silva, T.M.; Brait, V.H.; Drummond, G.R.; Sobey, C.G.; Miller, A.A. Nox2 oxidase activity accounts for the oxidative stress and vasomotor dysfunction in mouse cerebral arteries following ischemic stroke. PLoS One 2011, 6, e28393.
183. Acker, T.; Acker, H. Cellular oxygen sensing need in cns function: Physiological and pathological implications. J. Exp. Biol. 2004, 207, 3171-3188.
184. Goyal, P.; Weissmann, N.; Grimminger, F.; Hegel, C.; Bader, L.; Rose, F.; Fink, L.; Ghofrani, H.A.; Schermuly, R.T.; Schmidt, H.H.; et al. Upregulation of NAD(P)H oxidase 1 in hypoxia activates hypoxia-inducible factor 1 via increase in reactive oxygen species. Free Radic. Biol. Med. 2004, 36, 1279-1288.
185. Diebold, I.; Petry, A.; Hess, J.; Gorlach, A. The NAD(P)H oxidase subunit Nox4 is a new target gene of the hypoxia-inducible factor-1. Mol. Biol. Cell 2010, 21, 2087-2096.
186. Diebold, I.; Petry, A.; Sabrane, K.; Djordjevic, T.; Hess, J.; Gorlach, A. The HIF1 target gene NOX2 promotes angiogenesis through urotensin-II. J. Cell Sci. 2012, 125, 956-964.
187. Yuan, G.; Khan, S.A.; Luo, W.; Nanduri, J.; Semenza, G.L.; Prabhakar, N.R. Hypoxia-inducible factor 1 mediates increased expression of NAD(P)H oxidase-2 in response to intermittent hypoxia. J. Cell. Physiol. 2011, 226, 2925-2933.
188. Zhang, Z.G.; Chopp, M. Neurorestorative therapies for stroke: Underlying mechanisms and translation to the clinic. Lancet Neurol. 2009, 8, 491-500.
189. Mancuso, M.R.; Kuhnert, F.; Kuo, C.J. Developmental angiogenesis of the central nervous system. Lymphat. Res. Biol. 2008, 6, 173-180.
190. Jiang, F.; Zhang, Y.; Dusting, G.J. NADPH oxidase-mediated redox signaling: Roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol. Rev. 2011, 63, 218-242.
191. Ushio-Fukai, M. Redox signaling in angiogenesis: Role of NAD(P)H oxidase. Cardiovasc. Res. 2006, 71, 226-235.
192. Ushio-Fukai, M. VEGF signaling through NAD(P)H oxidase-derived ROS. Antioxid. Redox Signal. 2007, 9, 731-739.
193. Krupinski, J.; Kaluza, J.; Kumar, P.; Kumar, S.; Wang, J.M. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 1994, 25, 1794-1798.
194. Wei, L.; Erinjeri, J.P.; Rovainen, C.M.; Woolsey, T.A. Collateral growth and angiogenesis around cortical stroke. Stroke 2001, 32, 2179-2184.
195. Hayashi, T.; Noshita, N.; Sugawara, T.; Chan, P.H. Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J. Cereb. Blood Flow Metab. 2003, 23, 166-180.
196. Tojo, T.; Ushio-Fukai, M.; Yamaoka-Tojo, M.; Ikeda, S.; Patrushev, N.; Alexander, R.W. Role of gp91phox (Nox2)-containing NAD(P)H oxidase in angiogenesis in response to hindlimb ischemia. Circulation 2005, 111, 2347-2355.
197. Urao, N.; Inomata, H.; Razvi, M.; Kim, H.W.; Wary, K.; McKinney, R.; Fukai, T.; Ushio-Fukai, M. Role of Nox2-based NAD(P)H oxidase in bone marrow and progenitor cell function involved in neovascularization induced by hindlimb ischemia. Circ. Res. 2008, 103, 212-220.
198. Datla, S.R.; Peshavariya, H.; Dusting, G.J.; Mahadev, K.; Goldstein, B.J.; Jiang, F. Important role of Nox4 type NAD(P)H oxidase in angiogenic responses in human microvascular endothelial cells in vitro. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 2319-2324.
199. Chan, E.C.; Liu, G.S.; Roulston, C.L.; Lim, S.Y.; Dusting, G.J. NADPH Oxidase in Tissue Repair and Regeneration. In Systems of Biology and Oxidative Stress; Springer: New York, NY, USA, 2012.
200. Taylor, C.J.; Weston, R.M.; Dusting, G.J.; Roulston, C.L. NADPH oxidase and angiogenesis following endothelin-1 induced stroke in rats: Role for Nox2 in brain repair. Brain Sci. 2013, 3, 294-317.
201. Zhang, R.L.; Zhang, Z.G.; Chopp, M. Ischemic stroke and neurogenesis in the subventricular zone. Neuropharmacology 2008, 55, 345-352.
202. Manoonkitiwongsa, P.S.; Jackson-Friedman, C.; McMillan, P.J.; Schultz, R.L.; Lyden, P.D. Angiogenesis after stroke is correlated with increased numbers of macrophages: The clean-up hypothesis. J. Cereb. Blood Flow Metab. 2001, 21, 1223-1231.
203. Yu, S.W.; Friedman, B.; Cheng, Q.; Lyden, P.D. Stroke-evoked angiogenesis results in a transient population of microvessels. J. Cereb. Blood Flow Metab. 2007, 27, 755-763.
204. Tsatmali, M.; Walcott, E.C.; Makarenkova, H.; Crossin, K.L. Reactive oxygen species modulate the differentiation of neurons in clonal cortical cultures. Mol. Cell. Neurosci. 2006, 33, 345-357.
205. Knapp, L.T.; Klann, E. Role of reactive oxygen species in hippocampal long-term potentiation: Contributory or inhibitory? J. Neurosci. Res. 2002, 70, 1-7.
206. Zhao, C.; Deng, W.; Gage, F.H. Mechanisms and functional implications of adult neurogenesis. Cell 2008, 132, 645-660.
207. Pao, M.; Wiggs, E.A.; Anastacio, M.M.; Hyun, J.; DeCarlo, E.S.; Miller, J.T.; Anderson, V.L.; Malech, H.L.; Gallin, J.I.; Holland, S.M. Cognitive function in patients with chronic granulomatous disease: A preliminary report. Psychosomatics 2004, 45, 230-234.
208. Kishida, K.T.; Hoeffer, C.A.; Hu, D.; Pao, M.; Holland, S.M.; Klann, E. Synaptic plasticity deficits and mild memory impairments in mouse models of chronic granulomatous disease. Mol. Cell. Biol 2006, 26, 5908-5920.
209. Dickinson, B.C.; Peltier, J.; Stone, D.; Schaffer, D.V.; Chang, C.J. Nox2 redox signaling maintains essential cell populations in the brain. Nat. Chem. Biol. 2011, 7, 106-112.
210. Kim, J.A.; Neupane, G.P.; Lee, E.S.; Jeong, B.S.; Park, B.C.; Thapa, P. NADPH oxidase inhibitors: A patent review. Expert Opin. Ther. Pat. 2011, 21, 1147-1158.
211. Schroder, K.; Wandzioch, K.; Helmcke, I.; Brandes, R.P. Nox4 acts as a switch between differentiation and proliferation in preadipocytes. Arterioscler. Thromb. Vasc. Biol. 2009, 29, 239-245.
212. Peshavariya, H.; Jiang, F.; Taylor, C.J.; Selemidis, S.; Chang, C.W.; Dusting, G.J. Translation-linked mRNA destabilization accompanying serum-induced Nox4 expression in human endothelial cells. Antioxid. Redox Signal. 2009, 11, 2399-2408.
213. Van Den Worm, E.; Beukelman, C.J.; van den Berg, A.J.; Kroes, B.H.; Labadie, R.P.; van Dijk, H. Effects of methoxylation of apocynin and analogs on the inhibition of reactive oxygen species production by stimulated human neutrophils. Eur. J. Pharmacol. 2001, 433, 225-230.
214. Stolk, J.; Hiltermann, T.J.; Dijkman, J.H.; Verhoeven, A.J. Characteristics of the inhibition of NAD(P)H oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol. Am. J. Respir. Cell Mol. Biol. 1994, 11, 95-102.
215. Heumuller, S.; Wind, S.; Barbosa-Sicard, E.; Schmidt, H.H.; Busse, R.; Schroder, K.; Brandes, R.P. Apocynin is not an inhibitor of vascular NAD(P)H oxidases but an antioxidant. Hypertension 2008, 51, 211-217.
216. Touyz, R.M. Apocynin, NAD(P)H oxidase, and vascular cells: A complex matter. Hypertension 2008, 51, 172-174.
217. Weston, R.M.; Lin, B.; Dusting, G.J.; Roulston, C.L. Targeting oxidative stress injury after ischemic stroke in conscious rats: Limited benefits with apocynin highlights the need to incorporate long term recovery. Stroke Res. Treat. 2013, in press.
218. Weston, R.M.; Jones, N.M.; Jarrott, B.; Callaway, J.K. Inflammatory cell infiltration after endothelin-1-induced cerebral ischemia: Histochemical and myeloperoxidase correlation with temporal changes in brain injury. J. Cereb. Blood Flow Metab. 2007, 27, 100-114.
219. Simons, J.M.; Hart, B.A.; Ip Vai Ching, T.R.; van Dijk, H.; Labadie, R.P. Metabolic activation of natural phenols into selective oxidative burst agonists by activated human neutrophils. Free Radic. Biol. Med. 1990, 8, 251-258.
220. Aldieri, E.; Riganti, C.; Polimeni, M.; Gazzano, E.; Lussiana, C.; Campia, I.; Ghigo, D. Classical inhibitors of NOX NAD(P)H oxidases are not specific. Curr. Drug Metab. 2008, 9, 686-696.
221. Nagel, S.; Genius, J.; Heiland, S.; Horstmann, S.; Gardner, H.; Wagner, S. Diphenyleneiodonium and dimethylsulfoxide for treatment of reperfusion injury in cerebral ischemia of the rat. Brain Res. 2007, 1132, 210-217.
222. 2- and systolic blood pressure in mice. Circ. Res. 2001, 89, 408-414.
223. Park, L.; Anrather, J.; Girouard, H.; Zhou, P.; Iadecola, C. Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J. Cereb. Blood Flow Metab. 2007, 27, 1908-1918.
224. Cayatte, A.J.; Rupin, A.; Oliver-Krasinski, J.; Maitland, K.; Sansilvestri-Morel, P.; Boussard, M.F.; Wierzbicki, M.; Verbeuren, T.J.; Cohen, R.A. S17834, a new inhibitor of cell adhesion and atherosclerosis that targets NAD(P)H oxidase. Arterioscler. Thromb. Vasc. Biol. 2001, 21, 1577-1584.
225. Xu, S.; Jiang, B.; Hou, X.; Shi, C.; Bachschmid, M.M.; Zang, M.; Verbeuren, T.J.; Cohen, R.A. High-fat diet increases and the polyphenol, s17834, decreases acetylation of the sirtuin-1-dependent lysine-382 on p53 and apoptotic signaling in atherosclerotic lesion-prone aortic endothelium of normal mice. J. Cardiovasc. Pharmacol. 2011, 58, 263-271.
226. Wang, Q.; Tompkins, K.D.; Simonyi, A.; Korthuis, R.J.; Sun, A.Y.; Sun, G.Y. Apocynin protects against global cerebral ischemia-reperfusion-induced oxidative stress and injury in the gerbil hippocampus. Brain Res. 2006, 1090, 182-189.
227. Hultqvist, M.; Olsson, L.M.; Gelderman, K.A.; Holmdahl, R. The protective role of ROS in autoimmune disease. Trends Immunol. 2009, 30, 201-208.