Oxidative stress caused by an excess of reactive oxygen species (ROS) is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical setting. Targeting the source of oxidative stress may provide a superior therapeutic approach. The NADPH oxidases are a family of enzymes dedicated solely to ROS production and pre-clinical animal studies targeting NADPH oxidases have shown promising results. However there are multiple factors that need to be considered for future drug development: There are several homologues of the catalytic subunit of NADPH oxidase. All have differing physiological roles and may contribute differentially to oxidative damage after stroke. Additionally, the role of ROS in brain repair is largely unexplored, which should be taken into consideration when developing drugs that inhibit specific NADPH oxidases after injury. This article focuses on the current knowledge regarding NADPH oxidase after stroke including in vivo genetic and inhibitor studies. The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation.
References
[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, doi:10.1161/STROKEAHA.107.498725.
[2]
Dirnagl, U. Bench to bedside: The quest for quality in experimental stroke research. J. Cereb. Blood Flow Metab. 2006, 26, 1465–1478, doi:10.1038/sj.jcbfm.9600298.
[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, doi:10.1038/sj.bjp.0707626.
[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, doi:10.1002/ana.20741.
[7]
Feuerstein, G.Z.; Chavez, J. Translational medicine for stroke drug discovery: The pharmaceutical industry perspective. Stroke 2009, 40, S121–S125, doi:10.1161/STROKEAHA.108.535104.
[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, doi:10.1038/sj.jcbfm.9600516.
[9]
Proctor, P.H.; Tamborello, L.P. SAINT-I worked, but the neuroprotectant is not NXY-059. Stroke 2007, 38, e109, doi:10.1161/STROKEAHA.107.489161.
[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, doi:10.1046/j.0022-3042.2001.00675.x.
[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, doi:10.1002/jnr.20180.
[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, doi:10.1016/j.brainres.2006.06.082.
[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, doi:10.1016/j.neuroscience.2004.12.038.
[19]
Warner, D.S.; Sheng, H.; Batinic-Haberle, I. Oxidants, antioxidants and the ischemic brain. J. Exp. Biol. 2004, 207, 3221–3231, doi:10.1242/jeb.01022.
[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, doi:10.1113/jphysiol.2003.055913.
[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, doi:10.1046/j.1440-1681.2003.03920.x.
[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, doi:10.1016/j.freeradbiomed.2006.06.001.
[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, doi:10.1186/1750-2187-7-15.
[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, doi:10.1002/ana.21511.
[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, doi:10.1016/j.pbb.2007.04.015.
[29]
Manea, A. NADPH oxidase-derived reactive oxygen species: Involvement in vascular physiology and pathology. Cell Tissue Res. 2010, 342, 325–339, doi:10.1007/s00441-010-1060-y.
[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, doi:10.4155/fmc.09.140.
[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, doi:10.1016/0047-6374(92)90084-Q.
[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.
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, doi:10.1016/S0169-328X(97)00313-6.
[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, doi:10.1179/135100003125001378.
[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, doi:10.1046/j.0767-3981.2003.00209.x.
[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, doi:10.1007/s007010050201.
[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, doi:10.1038/sj.ejcn.1602248.
[52]
Amaro, S.; Chamorro, A. Translational stroke research of the combination of thrombolysis and antioxidant therapy. Stroke 2011, 42, 1495–1499, doi:10.1161/STROKEAHA.111.615039.
[53]
Margaill, I.; Plotkine, M.; Lerouet, D. Antioxidant strategies in the treatment of stroke. Free Radic. Biol. Med. 2005, 39, 429–443, doi:10.1016/j.freeradbiomed.2005.05.003.
[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, doi:10.1161/STROKEAHA.108.541128.
[55]
Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999, 30, 2752–2758, doi:10.1161/01.STR.30.12.2752.
[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, doi:10.1111/j.1476-5381.2009.00196.x.
[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, doi:10.1186/1471-2377-11-39.
[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, doi:10.1517/14656566.2010.493558.
[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, doi:10.1016/j.expneurol.2008.09.004.
[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, doi:10.1016/j.jstrokecerebrovasdis.2010.05.009.
[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, doi:10.1016/S0140-6736(94)92211-X.
[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, doi:10.7326/0003-4819-125-5-199609010-00005.
[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, doi:10.1007/BF03033450.
[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, doi:10.1016/j.ejphar.2008.01.046.
[66]
Firuzi, O.; Miri, R.; Tavakkoli, M.; Saso, L. Antioxidant therapy: Current status and future prospects. Curr. Med. Chem. 2011, 18, 3871–3888, doi:10.2174/092986711803414368.
[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, doi:10.1042/CS20110643.
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, doi:10.2174/092986708783497337.
[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, doi:10.2174/092986708784310431.
[72]
Wang, C.X.; Shuaib, A. Neuroprotective effects of free radical scavengers in stroke. Drugs Aging 2007, 24, 537–546, doi:10.2165/00002512-200724070-00002.
[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, doi:10.1016/j.bpa.2010.10.003.
[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, doi:10.1038/sj.jcbfm.9600369.
[75]
Brown, D.I.; Griendling, K.K. Nox proteins in signal transduction. Free Radic. Biol. Med. 2009, 47, 1239–1253, doi:10.1016/j.freeradbiomed.2009.07.023.
[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, doi:10.1089/ars.2006.8.1583.
[77]
Sorce, S.; Krause, K.H. Nox enzymes in the central nervous system: From signaling to disease. Antioxid. Redox Signal. 2009, 11, 2481–2504, doi:10.1089/ars.2009.2578.
[78]
Lambeth, J.D.; Krause, K.H.; Clark, R.A. Nox enzymes as novel targets for drug development. Semin. Immunopathol. 2008, 30, 339–363, doi:10.1007/s00281-008-0123-6.
[79]
Baldridge, C.W.; Gerard, R.W. The extra respiration of phagocytosis. Am. J. Physiol. 1933, 103, 235–236.
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, doi:10.1172/JCI107236.
[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, doi:10.1056/NEJM197403142901104.
[85]
Hohn, D.C.; Lehrer, R.I. NADPH oxidase deficiency in X-linked chronic granulomatous disease. J. Clin. Invest. 1975, 55, 707–713, doi:10.1172/JCI107980.
[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, doi:10.1006/abbi.2001.2642.
[88]
Vignais, P.V. The superoxide-generating NAD(P)H oxidase: Structural aspects and activation mechanism. Cell. Mol. Life Sci. 2002, 59, 1428–1459, doi:10.1007/s00018-002-8520-9.
[89]
Nauseef, W.M. Biological roles for the nox family NAD(P)H oxidases. J. Biol. Chem. 2008, 283, 16961–16965, doi:10.1074/jbc.R700045200.
[90]
Rada, B.; Leto, T.L. Oxidative innate immune defenses by Nox/Duox family NAD(P)H oxidases. Contrib. Microbiol. 2008, 15, 164–187, doi:10.1159/000136357.
[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.
Kikuchi, H.; Hikage, M.; Miyashita, H.; Fukumoto, M. NADPH oxidase subunit, gp91(phox) homologue, preferentially expressed in human colon epithelial cell. Gene 2000, 254, 237–243, doi:10.1016/S0378-1119(00)00258-4.
[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, doi:10.1073/pnas.130135897.
[97]
Lassegue, B.; Griendling, K.K. NADPH oxidases: Functions and pathologies in the vasculature. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 653–661, doi:10.1161/ATVBAHA.108.181610.
[98]
Banfi, B.; Molnar, G.; Maturana, A.; Steger, K.; Hegedus, B.; Demaurex, N.; Krause, K.H. A Ca2+-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, doi:10.1083/jcb.200103132.
[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, doi:10.1074/jbc.M501882200.
[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, doi:10.1016/j.pharmthera.2008.08.005.
[104]
Cheng, G.; Ritsick, D.; Lambeth, J.D. Nox3 regulation by NOXO1, p47phox, and p67phox. J. Biol. Chem. 2004, 279, 34250–34255, doi:10.1074/jbc.M400660200.
[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, doi:10.1016/j.freeradbiomed.2007.03.028.
[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, doi:10.1161/CIRCRESAHA.109.193722.
[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, doi:10.1016/j.cellsig.2005.03.023.
[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, doi:10.1111/j.1742-4658.2008.06488.x.
[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, doi:10.1074/jbc.M305968200.
[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, doi:10.1007/s00281-010-0221-0.
[112]
Lambeth, J.D. Nox enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 2004, 4, 181–189, doi:10.1038/nri1312.
[113]
Touyz, R.M. Reactive oxygen species in vascular biology: Role in arterial hypertension. Expert Rev. Cardiovasc. Ther. 2003, 1, 91–106, doi:10.1586/14779072.1.1.91.
[114]
Dale, D.C.; Boxer, L.; Liles, W.C. The phagocytes: Neutrophils and monocytes. Blood 2008, 112, 935–945, doi:10.1182/blood-2007-12-077917.
[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, doi:10.1002/glia.20504.
[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, doi:10.1097/00001756-199908200-00032.
[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, doi:10.1002/jnr.21571.
[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, doi:10.1016/j.mcn.2005.01.007.
[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, doi:10.1016/j.brainres.2005.01.066.
[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, doi:10.1016/S0006-8993(03)03364-X.
[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, doi:10.1016/j.yexcr.2010.03.021.
[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, doi:10.1016/j.nbd.2010.05.023.
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, doi:10.1006/abbi.1998.0658.
[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, doi:10.1523/JNEUROSCI.4306-04.2005.
[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, doi:10.1159/000235563.
[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, doi:10.1523/JNEUROSCI.3568-08.2008.
[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.
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, doi:10.1016/j.molmed.2008.09.003.
[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, doi:10.1161/01.RES.0000189301.10217.87.
[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, doi:10.1161/01.STR.0000163111.05825.0b.
[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, doi:10.1016/j.brainres.2009.06.056.
[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 Nox. Gene 2001, 269, 131–140, doi:10.1016/S0378-1119(01)00449-8.
[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, doi:10.1161/01.STR.0000112974.37028.58.
[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, doi:10.1161/01.ATV.0000142446.75898.44.
[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, doi:10.1111/j.1742-4658.2010.07700.x.
[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, doi:10.1161/CIRCRESAHA.109.215392.
[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, doi:10.1152/ajpheart.01270.2005.
[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, doi:10.1016/j.niox.2011.01.007.
[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, doi:10.1016/j.mcn.2011.01.009.
[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.
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, doi:10.1016/0165-5728(94)90010-8.
[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, doi:10.1038/jcbfm.2011.189.
[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, doi:10.1038/jcbfm.2010.14.
[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, doi:10.1038/sj.bjp.0706918.
[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, doi:10.1002/ana.22476.
[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, doi:10.1038/ni1096.
[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, doi:10.1161/01.STR.27.9.1578.
[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, doi:10.1007/BF01400874.
[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, doi:10.1016/j.nbd.2011.01.027.
[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, doi:10.1038/jcbfm.2009.47.
[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, doi:10.1016/j.brainres.2012.09.023.
[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, doi:10.1016/j.bbrc.2009.12.114.
[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, doi:10.1186/1742-2094-2-20.
[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, doi:10.1007/s00702-005-0389-y.
[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, doi:10.1098/rstb.2005.1766.
[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, doi:10.1016/0304-3940(89)90569-7.
[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, doi:10.1016/j.neuroscience.2008.03.090.
[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, doi:10.1016/j.brainres.2010.11.088.
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, doi:10.1016/j.nbd.2008.04.003.
[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, doi:10.1242/jeb.01075.
[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, doi:10.1016/j.freeradbiomed.2004.02.071.
[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, doi:10.1091/mbc.E09-12-1003.
[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, doi:10.1242/jcs.094060.
[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, doi:10.1002/jcp.22640.
[188]
Zhang, Z.G.; Chopp, M. Neurorestorative therapies for stroke: Underlying mechanisms and translation to the clinic. Lancet Neurol. 2009, 8, 491–500, doi:10.1016/S1474-4422(09)70061-4.
[189]
Mancuso, M.R.; Kuhnert, F.; Kuo, C.J. Developmental angiogenesis of the central nervous system. Lymphat. Res. Biol. 2008, 6, 173–180.
Ushio-Fukai, M. Redox signaling in angiogenesis: Role of NAD(P)H oxidase. Cardiovasc. Res. 2006, 71, 226–235, doi:10.1016/j.cardiores.2006.04.015.
[192]
Ushio-Fukai, M. VEGF signaling through NAD(P)H oxidase-derived ROS. Antioxid. Redox Signal. 2007, 9, 731–739, doi:10.1089/ars.2007.1556.
[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, doi:10.1161/01.STR.25.9.1794.
[194]
Wei, L.; Erinjeri, J.P.; Rovainen, C.M.; Woolsey, T.A. Collateral growth and angiogenesis around cortical stroke. Stroke 2001, 32, 2179–2184, doi:10.1161/hs0901.094282.
[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, doi:10.1161/01.CIR.0000164261.62586.14.
[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, doi:10.1161/CIRCRESAHA.108.176230.
[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, doi:10.1161/ATVBAHA.107.149450.
[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, doi:10.3390/brainsci3010294.
[201]
Zhang, R.L.; Zhang, Z.G.; Chopp, M. Ischemic stroke and neurogenesis in the subventricular zone. Neuropharmacology 2008, 55, 345–352, doi:10.1016/j.neuropharm.2008.05.027.
[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, doi:10.1016/j.mcn.2006.08.005.
[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, doi:10.1002/jnr.10371.
[206]
Zhao, C.; Deng, W.; Gage, F.H. Mechanisms and functional implications of adult neurogenesis. Cell 2008, 132, 645–660, doi:10.1016/j.cell.2008.01.033.
[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, doi:10.1176/appi.psy.45.3.230.
[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, doi:10.1128/MCB.00269-06.
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, doi:10.1016/S0014-2999(01)01516-3.
[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, doi:10.1161/HYPERTENSIONAHA.107.100214.
[216]
Touyz, R.M. Apocynin, NAD(P)H oxidase, and vascular cells: A complex matter. Hypertension 2008, 51, 172–174, doi:10.1161/HYPERTENSIONAHA.107.103200.
[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, doi:10.1038/sj.jcbfm.9600324.
[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, doi:10.2174/138920008786049285.
[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, doi:10.1016/j.brainres.2006.11.023.
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, doi:10.1038/sj.jcbfm.9600491.
[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, doi:10.1161/hq1001.096723.
[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, doi:10.1016/j.brainres.2006.03.060.
[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, doi:10.1016/j.it.2009.03.004.
