Oxidative Stress and the Use of Antioxidants in Stroke

Lozano, 2012, Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010, Lancet, 380, 2095, 10.1016/S0140-6736(12)61728-0

Murray, 2012, Disability-adjusted life years (dalys) for 291 diseases and injuries in 21 regions, 1990–2010: A systematic analysis for the global burden of disease study 2010, Lancet, 380, 2197, 10.1016/S0140-6736(12)61689-4

Townsend, N., Wickramasinghe, K., Bhatnagar, P., Smolina, K., Nichols, M., Leal, J., Luengo-Fernandez, R., and Rayner, M. (2012). Coronary Heart Disease Statistics, British Heart Foundation.

Li, 2013, Meta-analysis of clinical outcomes of intravenous recombinant tissue plasminogen activator for acute ischemic stroke: Within 3 h versus 3–4.5 h, Curr. Med. Res. Opin., 29, 1105, 10.1185/03007995.2013.818533

Adeoye, 2011, Recombinant tissue-type plasminogen activator use for ischemic stroke in the united states: A doubling of treatment rates over the course of 5 years, Stroke, 42, 1952, 10.1161/STROKEAHA.110.612358

2011, Scaling of brain metabolism with a fixed energy budget per neuron: Implications for neuronal activity, plasticity and evolution, PLoS One, 6, e17514, 10.1371/journal.pone.0017514

Pauwels, 1985, Effects of antimycin, glucose deprivation, and serum on cultures of neurons, astrocytes, and neuroblastoma cells, J. Neurochem., 44, 143, 10.1111/j.1471-4159.1985.tb07123.x

Uttara, 2009, Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options, Curr. Neuropharmacol., 7, 65, 10.2174/157015909787602823

Kahles, 2012, NADPH oxidases as therapeutic targets in ischemic stroke, Cell. Mol. Life Sci., 69, 2345, 10.1007/s00018-012-1011-8

Sanderson, 2013, Molecular mechanisms of ischemia-reperfusion injury in brain: Pivotal role of the mitochondrial membrane potential in reactive oxygen species generation, Mol. Neurobiol., 47, 9, 10.1007/s12035-012-8344-z

Vergeade, 2012, Xanthine oxidase contributes to mitochondrial ros generation in an experimental model of cocaine-induced diastolic dysfunction, J. Cardiovasc. Pharmacol., 60, 538, 10.1097/FJC.0b013e318271223c

Rice, 2011, H2O2: A dynamic neuromodulator, Neuroscientist, 17, 389, 10.1177/1073858411404531

Liu, 2004, Interstitial pO2 in ischemic penumbra and core are differentially affected following transient focal cerebral ischemia in rats, J. Cereb. Blood Flow Metab., 24, 343, 10.1097/01.WCB.0000110047.43905.01

Ying, 1999, Acidosis potentiates oxidative neuronal death by multiple mechanisms, J. Neurochem., 73, 1549, 10.1046/j.1471-4159.1999.0731549.x

Stanika, 2012, Comparative impact of voltage-gated calcium channels and nmda receptors on mitochondria-mediated neuronal injury, J. Neurosci., 32, 6642, 10.1523/JNEUROSCI.6008-11.2012

Yamato, 2003, Application of in vivo ESR spectroscopy to measurement of cerebrovascular ROS generation in stroke, Free Radic. Biol. Med., 35, 1619, 10.1016/j.freeradbiomed.2003.09.013

Peters, 1998, Increased formation of reactive oxygen species after permanent and reversible middle cerebral artery occlusion in the rat, J. Cereb. Blood Flow Metab., 18, 196, 10.1097/00004647-199802000-00011

Chen, 2008, Ischemic defects in the electron transport chain increase the production of reactive oxygen species from isolated rat heart mitochondria, Am. J. Physiol. Cell. Physiol., 294, C460, 10.1152/ajpcell.00211.2007

Niatsetskaya, 2012, The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice, J. Neurosci., 32, 3235, 10.1523/JNEUROSCI.6303-11.2012

Chouchani, 2013, Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I, Nat. Med., 19, 753, 10.1038/nm.3212

Chen, 2009, Inhibition of NADPH oxidase is neuroprotective after ischemia-reperfusion, J. Cereb. Blood Flow Metab., 29, 1262, 10.1038/jcbfm.2009.47

Bokoch, 2003, NADPH oxidases: Not just for leukocytes anymore!, Trends Biochem. Sci., 28, 502, 10.1016/S0968-0004(03)00194-4

Cheng, 2004, Nox3 regulation by NOXO1, p47phox, and p67phox, J. Biol. Chem., 279, 34250, 10.1074/jbc.M400660200

Matsushima, 2013, Increased oxidative stress in the nucleus caused by Nox4 mediates oxidation of HDAC4 and cardiac hypertrophy, Circ. Res., 112, 651, 10.1161/CIRCRESAHA.112.279760

Granger, 1981, Superoxide radicals in feline intestinal ischemia, Gastroenterology, 81, 22, 10.1016/0016-5085(81)90648-X

Parks, 1986, Xanthine oxidase: Biochemistry, distribution and physiology, Acta Physiol. Scand. Suppl., 548, 87

Crack, 2005, Reactive oxygen species and the modulation of stroke, Free Radic. Biol. Med., 38, 1433, 10.1016/j.freeradbiomed.2005.01.019

Can, 2004, Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia, Stroke, 35, 1449, 10.1161/01.STR.0000126044.83777.f4

Nelson, 1992, Oxygen radicals in cerebral ischemia, Am. J. Physiol., 263, H1356

McCracken, 2000, The lipid peroxidation by-product 4-hydroxynonenal is toxic to axons and oligodendrocytes, J. Cereb. Blood Flow Metab., 20, 1529, 10.1097/00004647-200011000-00002

Matsuda, 2009, Alterations of oxidative stress markers and apoptosis markers in the striatum after transient focal cerebral ischemia in rats, J. Neural Transm., 116, 395, 10.1007/s00702-009-0194-0

Liu, 1996, Damage, repair, and mutagenesis in nuclear genes after mouse forebrain ischemia-reperfusion, J. Neurosci., 16, 6795, 10.1523/JNEUROSCI.16-21-06795.1996

Chen, 1997, Early detection of DNA strand breaks in the brain after transient focal ischemia: Implications for the role of DNA damage in apoptosis and neuronal cell death, J. Neurochem., 69, 232, 10.1046/j.1471-4159.1997.69010232.x

Nagayama, 2000, Activation of poly(adp-ribose) polymerase in the rat hippocampus may contribute to cellular recovery following sublethal transient global ischemia, J. Neurochem., 74, 1636, 10.1046/j.1471-4159.2000.0741636.x

Kawase, 1999, Reduction of apurinic/apyrimidinic endonuclease expression after transient global cerebral ischemia in rats: Implication of the failure of DNA repair in neuronal apoptosis, Stroke, 30, 441, 10.1161/01.STR.30.2.441

Kirkland, 2002, A bax-induced pro-oxidant state is critical for cytochrome c release during programmed neuronal death, J. Neurosci., 22, 6480, 10.1523/JNEUROSCI.22-15-06480.2002

Sugawara, 2002, Overexpression of SOD1 protects vulnerable motor neurons after spinal cord injury by attenuating mitochondrial cytochrome c release, FASEB J., 16, 1997, 10.1096/fj.02-0251fje

Croall, 1991, Calcium-activated neutral protease (calpain) system: Structure, function, and regulation, Physiol. Rev., 71, 813, 10.1152/physrev.1991.71.3.813

Scorrano, 2001, Arachidonic acid causes cell death through the mitochondrial permeability transition. Implications for tumor necrosis factor-alpha aopototic signaling, J. Biol. Chem., 276, 12035, 10.1074/jbc.M010603200

Enari, 1998, A caspase-activated dnase that degrades DNA during apoptosis, and its inhibitor icad, Nature, 391, 43, 10.1038/34112

Sprengart, 1998, Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis, J. Biol. Chem., 273, 9357, 10.1074/jbc.273.16.9357

Hanus, 2008, The major apoptotic endonuclease DFF40/CAD is a deoxyribose-specific and double-strand-specific enzyme, Apoptosis, 13, 377, 10.1007/s10495-008-0183-z

Widlak, 2000, Cleavage preferences of the apoptotic endonuclease DFF40 (caspase-activated dnase or nuclease) on naked DNA and chromatin substrates, J. Biol. Chem., 275, 8226, 10.1074/jbc.275.11.8226

Dalton, 1999, Regulation of gene expression by reactive oxygen, Annu. Rev. Pharmacol. Toxicol., 39, 67, 10.1146/annurev.pharmtox.39.1.67

Pautz, 2010, Regulation of the expression of inducible nitric oxide synthase, Nitric Oxide, 23, 75, 10.1016/j.niox.2010.04.007

Kim, 2010, Ischemic preconditioning mediates cyclooxygenase-2 expression via nuclear factor-kappa B activation in mixed cortical neuronal cultures, Transl. Stroke Res., 1, 40, 10.1007/s12975-009-0006-8

Hsieh, 2010, Transforming growth factor-beta1 induces matrix metalloproteinase-9 and cell migration in astrocytes: Roles of ros-dependent ERK- and JNK-NF-kappaB pathways, J. Neuroinflamm., 7, 88, 10.1186/1742-2094-7-88

Park, 2013, Prostaglandin e(2)-induced intercellular adhesion molecule-1 expression is mediated by cAMP/Epac signalling modules in bEnd.3 brain endothelial cells, Br. J. Pharmacol., 169, 604, 10.1111/bph.12103

Deng, 2001, Novel role for JNK as a stress-activated Bcl2 kinase, J. Biol. Chem., 276, 23681, 10.1074/jbc.M100279200

Fan, 2001, Role of mitogen-activated protein kinases in the response of tumor cells to chemotherapy, Drug Resist. Updat, 4, 253, 10.1054/drup.2001.0214

Soberanes, 2009, Mitochondrial complex III-generated oxidants activate ASK1 and JNK to induce alveolar epithelial cell death following exposure to particulate matter air pollution, J. Biol. Chem., 284, 2176, 10.1074/jbc.M808844200

Kuiper, 1997, The blood-brain barrier in neuroinflammatory diseases, Pharmacol. Rev., 49, 143

Grieb, 1985, O2 exchange between blood and brain tissues studied with 18O2 indicator-dilution technique, J. Appl. Physiol., 58, 1929, 10.1152/jappl.1985.58.6.1929

Kastrup, 2000, Serial mri after transient focal cerebral ischemia in rats: Dynamics of tissue injury, blood-brain barrier damage, and edema formation, Stroke, 31, 1965, 10.1161/01.STR.31.8.1965

Rosell, 2008, Mmp-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke, Stroke, 39, 1121, 10.1161/STROKEAHA.107.500868

Cortez, 2007, Il-17 stimulates MMP-1 expression in primary human cardiac fibroblasts via p38 MAPK- and ERK1/2-dependent C/EBP-β, NF-κB, and AP-1 activation, Am. J. Physiol. Heart Circ. Physiol., 293, H3356, 10.1152/ajpheart.00928.2007

Mark, 2002, Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation, Am. J. Physiol. Heart Circ. Physiol., 282, H1485, 10.1152/ajpheart.00645.2001

Huber, 2001, Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression, Am. J. Physiol. Heart Circ. Physiol., 280, H1241, 10.1152/ajpheart.2001.280.3.H1241

Yamagata, 2004, Hypoxia-induced changes in tight junction permeability of brain capillary endothelial cells are associated with IL-1beta and nitric oxide, Neurobiol. Dis., 17, 491, 10.1016/j.nbd.2004.08.001

Pokutta, 1994, Conformational changes of the recombinant extracellular domain of E-cadherin upon calcium binding, Eur. J. Biochem., 223, 1019, 10.1111/j.1432-1033.1994.tb19080.x

Cipolla, 2004, Transcellular transport as a mechanism of blood-brain barrier disruption during stroke, Front. Biosci., 9, 777, 10.2741/1282

Xu, 2005, Leukocyte diapedesis in vivo induces transient loss of tight junction protein at the blood-retina barrier, Investig. Ophthalmol. Vis. Sci., 46, 2487, 10.1167/iovs.04-1333

Konsman, 2007, (Peri)vascular production and action of pro-inflammatory cytokines in brain pathology, Clin. Sci., 112, 1, 10.1042/CS20060043

Peerschke, 2010, Complement activation on platelets: Implications for vascular inflammation and thrombosis, Mol. Immunol., 47, 2170, 10.1016/j.molimm.2010.05.009

Pinsky, 1996, Hypoxia-induced exocytosis of endothelial cell weibel-palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation, J. Clin. Investig., 97, 493, 10.1172/JCI118440

Yilmaz, 2010, Leukocyte recruitment and ischemic brain injury, Neuromol. Med., 12, 193, 10.1007/s12017-009-8074-1

Atochin, 2007, The phosphorylation state of enos modulates vascular reactivity and outcome of cerebral ischemia in vivo, J. Clin. Investig., 117, 1961, 10.1172/JCI29877

Mori, 1991, Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons, Stroke, 22, 1276, 10.1161/01.STR.22.10.1276

Melani, 2005, ATP extracellular concentrations are increased in the rat striatum during in vivo ischemia, Neurochem. Int., 47, 442, 10.1016/j.neuint.2005.05.014

Korcok, 2004, Extracellular nucleotides act through P2X7 receptors to activate NF-kappaB in osteoclasts, J. Bone Miner. Res., 19, 642, 10.1359/JBMR.040108

Lyons, 2007, CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: A role for IL-4, J. Neurosci., 27, 8309, 10.1523/JNEUROSCI.1781-07.2007

Denes, 2008, Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse, J. Cereb. Blood Flow Metab., 28, 1707, 10.1038/jcbfm.2008.64

Chen, 2010, Sterile inflammation: Sensing and reacting to damage, Nat. Rev. Immunol., 10, 826, 10.1038/nri2873

Marsh, 2009, Toll-like receptor signaling in endogenous neuroprotection and stroke, Neuroscience, 158, 1007, 10.1016/j.neuroscience.2008.07.067

Facchinetti, 1998, Free radicals as mediators of neuronal injury, Cell. Mol. Neurobiol., 18, 667, 10.1023/A:1020685903186

Margaill, 2005, Antioxidant strategies in the treatment of stroke, Free Radic. Biol. Med., 39, 429, 10.1016/j.freeradbiomed.2005.05.003

Tang, 2007, Apocynin attenuates cerebral infarction after transient focal ischaemia in rats, J. Int. Med. Res., 35, 517, 10.1177/147323000703500411

Genovese, 2011, Modulation of NADPH oxidase activation in cerebral ischemia/reperfusion injury in rats, Brain Res., 1372, 92, 10.1016/j.brainres.2010.11.088

McCann, 2008, Early increase of NOX4 NADPH oxidase and superoxide generation following endothelin-1-induced stroke in conscious rats, J. Neurosci. Res., 86, 2524, 10.1002/jnr.21700

Yoshioka, 2011, NADPH oxidase mediates striatal neuronal injury after transient global cerebral ischemia, J. Cereb. Blood Flow Metab., 31, 868, 10.1038/jcbfm.2010.166

Serrander, 2007, NOX4 activity is determined by MRNA levels and reveals a unique pattern of ros generation, Biochem. J., 406, 105, 10.1042/BJ20061903

Chen, 2011, NADPH oxidase is involved in post-ischemic brain inflammation, Neurobiol. Dis., 42, 341, 10.1016/j.nbd.2011.01.027

Brait, 2011, NOX2 oxidase activity accounts for the oxidative stress and vasomotor dysfunction in mouse cerebral arteries following ischemic stroke, PLoS One, 6, e0028393

Kleinschnitz, 2010, Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration, PLoS Biol., 8, e1000479, 10.1371/journal.pbio.1000479

Suzuki, Y., Hattori, K., Hamanaka, J., Murase, T., Egashira, Y., Mishiro, K., Ishiguro, M., Tsuruma, K., Hirose, Y., and Tanaka, H. (2012). Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia. Sci. Rep., 2.

Jackman, 2009, Importance of NOX1 for angiotensin II-induced cerebrovascular superoxide production and cortical infarct volume following ischemic stroke, Brain Res., 1286, 215, 10.1016/j.brainres.2009.06.056

Kahles, 2010, NADPH oxidase NOX1 contributes to ischemic injury in experimental stroke in mice, Neurobiol. Dis., 40, 185, 10.1016/j.nbd.2010.05.023

Radermacher, 2012, The 1027th target candidate in stroke: Will NADPH oxidase hold up?, Exp. Transl. Stroke Med., 4, 11, 10.1186/2040-7378-4-11

Altenhofer, S., Radermacher, K.A., Kleikers, P., Wingler, K., and Schmidt, H.H. (2014). Evolution of NADPH oxidase inhibitors: Selectivity and mechanisms for target engagement. Antioxid. Redox Signal., in press.

Khan, 2008, Allopurinol treatment reduces arterial wave reflection in stroke survivors, Cardiovasc. Ther., 26, 247, 10.1111/j.1755-5922.2008.00057.x

Muir, 2006, Glutamate-based therapeutic approaches: Clinical trials with nmda antagonists, Curr. Opin. Pharmacol., 6, 53, 10.1016/j.coph.2005.12.002

Dawson, 2009, The effect of allopurinol on the cerebral vasculature of patients with subcortical stroke; a randomized trial, Br. J. Clin. Pharmacol., 68, 662, 10.1111/j.1365-2125.2009.03497.x

Park, 1994, Dose-response analysis of the effect of 21-aminosteroid tirilazad mesylate (U-74006F) upon neurological outcome and ischemic brain damage in permanent focal cerebral ischemia, Brain Res., 645, 157, 10.1016/0006-8993(94)91649-7

Xue, 1992, Tirilazad reduces cortical infarction after transient but not permanent focal cerebral ischemia in rats, Stroke, 23, 894, 10.1161/01.STR.23.6.894

Sena, 2007, Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke, Stroke, 38, 388, 10.1161/01.STR.0000254462.75851.22

RANTTAS (1996). A randomized trial of tirilazad mesylate in patients with acute stroke (ranttas). The ranttas investigators. Stroke, 27, 1453–1458.

Fleishaker, 1995, Effect of gender and menopausal status on the pharmacokinetics of tirilazad mesylate in healthy subjects, Am. J. Ther., 2, 553, 10.1097/00045391-199508000-00007

Kuroda, 1999, Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat, J. Cereb. Blood Flow Metab., 19, 778, 10.1097/00004647-199907000-00008

Zhao, 2001, NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat, Brain Res., 909, 46, 10.1016/S0006-8993(01)02618-X

Sydserff, 2002, Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window, Br. J. Pharmacol., 135, 103, 10.1038/sj.bjp.0704449

Marshall, 2001, NXY-059, a free radical—Trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species, Stroke, 32, 190, 10.1161/01.STR.32.1.190

Marshall, 2003, Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 h after occlusion, Stroke, 34, 2228, 10.1161/01.STR.0000087790.79851.A8

Lees, 2006, Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial, Stroke, 37, 2970, 10.1161/01.STR.0000249410.91473.44

Shuaib, 2007, NXY-059 for the treatment of acute ischemic stroke, N. Engl. J. Med., 357, 562, 10.1056/NEJMoa070240

Koziol, 2006, On the analysis and interpretation of outcome measures in stroke clinical trials: Lessons from the saint i study of NXY-059 for acute ischemic stroke, Stroke, 37, 2644, 10.1161/01.STR.0000241106.81293.2b

Saver, 2007, Clinical impact of NXY-059 demonstrated in the saint I trial: Derivation of number needed to treat for benefit over entire range of functional disability, Stroke, 38, 1515, 10.1161/01.STR.0000263135.47779.9e

Fisher, 2006, NXY-059: Brain or vessel protection, Stroke, 37, 2189, 10.1161/01.STR.0000230598.31774.7a

Watanabe, 2004, Research and development of the free radical scavenger edaravone as a neuroprotectant, Yakugaku Zasshi, 124, 99, 10.1248/yakushi.124.99

Lapchak, 2010, A critical assessment of edaravone acute ischemic stroke efficacy trials: Is edaravone an effective neuroprotective therapy?, Exp. Opin. Pharmacother., 11, 1753, 10.1517/14656566.2010.493558

Higashi, 2009, Edaravone for the treatment of acute cerebral infarction: Role of endothelium-derived nitric oxide and oxidative stress, Exp. Opin. Pharmacother., 10, 323, 10.1517/14656560802636888

Watanabe, 1994, Protective effects of MCI-186 on cerebral-ischemia—Possible involvement of free-radical scavenging and antioxidant actions, J. Pharmacol. Exp. Ther., 268, 1597

Wu, 2000, MCI-186: Further histochemical and biochemical evidence of neuroprotection, Life Sci., 67, 2387, 10.1016/S0024-3205(00)00824-9

Jin, 2002, Combined argatroban and edaravone caused additive neuroprotection against 15 min of forebrain ischemia in gerbils, Neurosci. Res., 43, 75, 10.1016/S0168-0102(02)00019-6

Ikeda, 2013, Effects of edaravone, a free radical scavenger, on photochemically induced cerebral infarction in a rat hemiplegic model, Sci. World J., 2013, 175280, 10.1155/2013/175280

Otomo, 2003, Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction—Randomized, placebo-controlled, double-blind study at multicenters, Cerebrovas. Dis., 15, 222, 10.1159/000069318

Inatomi, 2006, Efficacy of edaravone in cardioembolic stroke, Int. Med., 45, 253, 10.2169/internalmedicine.45.1423

Nakase, 2011, Free radical scavenger, edaravone, reduces the lesion size of lacunar infarction in human brain ischemic stroke, BMC Neurol., 11, 39, 10.1186/1471-2377-11-39

Warner, 2004, Oxidants, antioxidants and the ischemic brain, J. Exp. Biol., 207, 3221, 10.1242/jeb.01022

Gaspar, 2009, Neuroprotective effect of adenoviral catalase gene transfer in cortical neuronal cultures, Brain Res., 1270, 1, 10.1016/j.brainres.2009.03.006

Kim, 2009, Transduced human PEP-1-catalase fusion protein attenuates ischemic neuronal damage, Free Radic. Biol. Med., 47, 941, 10.1016/j.freeradbiomed.2009.06.036

Gu, 2004, Catalase over-expression protects striatal neurons from transient focal cerebral ischemia, Neuroreport, 15, 413, 10.1097/00001756-200403010-00006

Reuhl, 1998, Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage, Brain Res. Mol. Brain Res., 53, 333, 10.1016/S0169-328X(97)00313-6

Ishibashi, 2002, Glutathione peroxidase inhibits cell death and glial activation following experimental stroke, Brain Res. Mol. Brain Res., 109, 34, 10.1016/S0169-328X(02)00459-X

Crack, 2001, Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (GPX-1) knockout mouse brain in response to ischemia/reperfusion injury, J. Neurochem., 78, 1389, 10.1046/j.1471-4159.2001.00535.x

Fujimura, 2000, The cytosolic antioxidant copper/zinc-superoxide dismutase prevents the early release of mitochondrial cytochrome c in ischemic brain after transient focal cerebral ischemia in mice, J. Neurosci., 20, 2817, 10.1523/JNEUROSCI.20-08-02817.2000

Kondo, 1997, Edema formation exacerbates neurological and histological outcomes after focal cerebral ischemia in cuzn-superoxide dismutase gene knockout mutant mice, Brain Edema X, 70, 62, 10.1007/978-3-7091-6837-0_19

Davis, 2007, Gene therapy using SOD1 protects striatal neurons from experimental stroke, Neurosci. Lett., 411, 32, 10.1016/j.neulet.2006.08.089

Sheng, 1999, Mice overexpressing extracellular superoxide dismutase have increased resistance to focal cerebral ischemia, Neuroscience, 88, 185, 10.1016/S0306-4522(98)00208-5

Li, 1995, Oxidative modification of cupro-zinc superoxide dismutase by reactive oxygen species, Sheng Li Ke Xue Jin Zhan, 26, 50

Kim, 2002, Involvement of superoxide in excitotoxicity and DNA fragmentation in striatal vulnerability in mice after treatment with the mitochondrial toxin, 3-nitropropionic acid, J. Cereb. Blood Flow Metab., 22, 798, 10.1097/00004647-200207000-00005

Maier, 2006, A new approach for the investigation of reperfusion-related brain injury, Biochem. Soc. Trans., 34, 1366, 10.1042/BST0341366

Jung, 2009, STAT3 regulates the transcription of the mouse Mn-SOD gene as a neuroprotectant in cerebral ischemic reperfusion, J. Cereb. Blood Flow Metab., 29, S565

Jung, 2011, Neuroprotection by interleukin-6 is mediated by signal transducer and activator of transcription 3 and antioxidative signaling in ischemic stroke, Stroke, 42, 3574, 10.1161/STROKEAHA.111.626648

Namura, 2001, Ebselen reduces cytochrome c release from mitochondria and subsequent DNA fragmentation after transient focal cerebral ischemia in mice, Stroke, 32, 1906, 10.1161/01.STR.32.8.1906

Imai, 2001, Ebselen protects both gray and white matter in a rodent model of focal cerebral ischemia, Stroke, 32, 2149, 10.1161/hs0901.095725

Takasago, 1997, Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion, Br. J. Pharmacol., 122, 1251, 10.1038/sj.bjp.0701426

Yamaguchi, 1998, Ebselen in acute ischemic stroke: A placebo-controlled, double-blind clinical trial. Ebselen study group, Stroke, 29, 12, 10.1161/01.STR.29.1.12

Ohsawa, 2007, Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals, Nat. Med., 13, 688, 10.1038/nm1577

Singhal, 2002, Effects of normobaric hyperoxia in a rat model of focal cerebral ischemia-reperfusion, J. Cereb. Blood Flow Metab., 22, 861, 10.1097/00004647-200207000-00011

Singhal, 2002, Normobaric hyperoxia reduces MRI diffusion abnormalities and infarct size in experimental stroke, Neurology, 58, 945, 10.1212/WNL.58.6.945

Esposito, 2013, Effects of normobaric oxygen on the progression of focal cerebral ischemia in rats, Exp. Neurol., 249, 33, 10.1016/j.expneurol.2013.08.005

Kim, 2005, Normobaric hyperoxia extends the reperfusion window in focal cerebral ischemia, Ann. Neurol., 57, 571, 10.1002/ana.20430

Geng, 2013, Synergetic neuroprotection of normobaric oxygenation and ethanol in ischemic stroke through improved oxidative mechanism, Stroke, 44, 1418, 10.1161/STROKEAHA.111.000315

Geng, 2013, Reduced apoptosis by combining normobaric oxygenation with ethanol in transient ischemic stroke, Brain Res., 1531, 17, 10.1016/j.brainres.2013.07.051

Dalkara, 1994, The complex role of nitric oxide in the pathophysiology of focal cerebral ischemia, Brain Pathol., 4, 49, 10.1111/j.1750-3639.1994.tb00810.x

Dalkara, 1994, Dual role of nitric oxide in focal cerebral ischemia, Neuropharmacology, 33, 1447, 10.1016/0028-3908(94)90048-5

Huang, 2004, Ischemic stroke: Acidotoxicity is a perpetrator, Cell, 118, 665, 10.1016/j.cell.2004.09.004

Bonnin, 2012, Inhaled nitric oxide reduces brain damage by collateral recruitment in a neonatal stroke model, Stroke, 43, 3078, 10.1161/STROKEAHA.112.664243

Terpolilli, 2012, Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles, Circ. Res., 110, 727, 10.1161/CIRCRESAHA.111.253419

Lesage, 1996, Lubeluzole, a novel long-term neuroprotectant, inhibits the glutamate-activated nitric oxide synthase pathway, J. Pharmacol. Exp. Ther., 279, 759

Ashton, 1997, Altered Na+-channel function as an in vitro model of the ischemic penumbra: Action of lubeluzole and other neuroprotective drugs, Brain Res., 745, 210, 10.1016/S0006-8993(96)01094-3

Maiese, 1997, Neuroprotection of lubeluzole is mediated through the signal transduction pathways of nitric oxide, J. Neurochem., 68, 710, 10.1046/j.1471-4159.1997.68020710.x

Keersmaekers, 1996, Lubeluzole protects sensorimotor function and reduces infarct size in a photochemical stroke model in rats, J. Pharmacol. Exp. Ther., 279, 748

Aronowski, 1996, Treatment of experimental focal ischemia in rats with lubeluzole, Neuropharmacology, 35, 689, 10.1016/0028-3908(96)84640-5

Diener, 1996, Lubeluzole in acute ischemic stroke. A double-blind, placebo-controlled phase II trial. Lubeluzole international study group, Stroke, 27, 76, 10.1161/01.STR.27.1.76

Grotta, 1997, Lubeluzole treatment of acute ischemic stroke. The US and Canadian lubeluzole ischemic stroke study group, Stroke, 28, 2338, 10.1161/01.STR.28.12.2338

Diener, 1998, Multinational randomised controlled trial of lubeluzole in acute ischaemic stroke. European and Australian lubeluzole ischaemic stroke study group, Cerebrovasc. Dis, 8, 172, 10.1159/000015847

Diener, 2000, Lubeluzole in acute ischemic stroke treatment: A double-blind study with an 8-h inclusion window comparing a 10-mg daily dose of lubeluzole with placebo, Stroke, 31, 2543, 10.1161/01.STR.31.11.2543

Gandolfo, C., Sandercock, P., and Conti, M. (2002). Lubeluzole for acute ischaemic stroke. Cochrane Database Syst. Rev.

Weisiger, 1973, Mitochondrial superoxide simutase. Site of synthesis and intramitochondrial localization, J. Biol. Chem., 248, 4793, 10.1016/S0021-9258(19)43735-6

Abramov, 2007, Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation, J. Neurosci., 27, 1129, 10.1523/JNEUROSCI.4468-06.2007

Murphy, 2014, Antioxidants as therapies: Can we improve on nature?, Free Radic. Biol. Med., 66, 20, 10.1016/j.freeradbiomed.2013.04.010

Pan, 2005, Mitochondrially targeted vitamin E and vitamin E mitigate ethanol-mediated effects on cerebellar granule cell antioxidant defense systems, Brain Res., 1052, 202, 10.1016/j.brainres.2005.06.030

Dhanasekaran, 2004, Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis, J. Biol. Chem., 279, 37575, 10.1074/jbc.M404003200

Murphy, 2007, Targeting antioxidants to mitochondria by conjugation to lipophilic cations, Annu. Rev. Pharmacol. Toxicol., 47, 629, 10.1146/annurev.pharmtox.47.120505.105110

Kelso, 2002, Prevention of mitochondrial oxidative damage using targeted antioxidants, Increasing Healthy Life Span, 959, 263

Smith, 2010, Animal and human studies with the mitochondria-targeted antioxidant mitoq, Ann. N. Y. Acad.Sci., 1201, 96, 10.1111/j.1749-6632.2010.05627.x

Adlam, 2005, Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury, FASEB J., 19, 1088, 10.1096/fj.05-3718com

Graham, 2009, Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy, Hypertension, 54, 322, 10.1161/HYPERTENSIONAHA.109.130351

McLachlan, 2014, Combined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function, J. Hypertens., 32, 555, 10.1097/HJH.0000000000000054

Wani, 2011, Protective efficacy of mitochondrial targeted antioxidant mitoq against dichlorvos induced oxidative stress and cell death in rat brain, Neuropharmacology, 61, 1193, 10.1016/j.neuropharm.2011.07.008

Hobbs, 2008, Neonatal rat hypoxia-ischemia: Effect of the anti-oxidant mitoquinol, and S-PBN, Pediatr. Int., 50, 481, 10.1111/j.1442-200X.2008.02705.x

Miura, 2009, Ascorbic acid protects the newborn rat brain from hypoxic-ischemia, Brain Dev., 31, 307, 10.1016/j.braindev.2008.06.010

Ducruet, 2011, Preclinical evaluation of postischemic dehydroascorbic acid administration in a large-animal stroke model, Transl. Stroke Res., 2, 399, 10.1007/s12975-011-0084-2

Zhang, 2011, Increased oxidative stress is responsible for severer cerebral infarction in stroke-prone spontaneously hypertensive rats, CNS Neurosci. Ther., 17, 590, 10.1111/j.1755-5949.2011.00271.x

Yokoyama, 2000, Serum vitamin C concentration was inversely associated with subsequent 20-year incidence of stroke in a japanese rural community. The shibata study, Stroke, 31, 2287, 10.1161/01.STR.31.10.2287

Myint, 2008, Plasma vitamin C concentrations predict risk of incident stroke over 10 year in 20,649 participants of the european prospective investigation into cancer norfolk prospective population study, Am. J. Clin. Nutr., 87, 64, 10.1093/ajcn/87.1.64

Kubota, 2011, Dietary intakes of antioxidant vitamins and mortality from cardiovascular disease: The Japan collaborative cohort study (JACC) study, Stroke, 42, 1665, 10.1161/STROKEAHA.110.601526

Heart Protection Study Collaborative Group (2002). MRC/BHF heart protection study of antioxidant vitamin supplementation in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet, 360, 23–33.

Cook, 2007, A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: Results from the women’s antioxidant cardiovascular study, Arch. Intern. Med., 167, 1610, 10.1001/archinte.167.15.1610

Sesso, 2008, Vitamins E and C in the prevention of cardiovascular disease in men: The physicians’ health study II randomized controlled trial, JAMA, 300, 2123, 10.1001/jama.2008.600

Schurks, M., Glynn, R.J., Rist, P.M., Tzourio, C., and Kurth, T. (2010). Effects of vitamin E on stroke subtypes: Meta-analysis of randomised controlled trials. Br. Med. J.

Bin, 2011, The role of vitamin E (tocopherol) supplementation in the prevention of stroke a meta-analysis of 13 randomised controlled trials, Thromb. Haemost., 105, 579, 10.1160/TH10-11-0729

Wang, 1995, Purification and characterization of hypoxia-inducible factor 1, J. Biol. Chem., 270, 1230, 10.1074/jbc.270.3.1230

Bernaudin, 2002, Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain, J. Cereb. Blood Flow Metab., 22, 393, 10.1097/00004647-200204000-00003

Jones, 2001, Hypoxic preconditioning induces changes in HIF-1 target genes in neonatal rat brain, J. Cereb. Blood Flow Metab., 21, 1105, 10.1097/00004647-200109000-00008

Prass, 2002, Desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro, J. Cereb. Blood Flow Metab., 22, 520, 10.1097/00004647-200205000-00003

Freret, 2006, Delayed administration of deferoxamine reduces brain damage and promotes functional recovery after transient focal cerebral ischemia in the rat, Eur. J. Neurosci., 23, 1757, 10.1111/j.1460-9568.2006.04699.x

Wang, 2008, Effects of neuroglobin overexpression on acute brain injury and long-term outcomes after focal cerebral ischemia, Stroke, 39, 1869, 10.1161/STROKEAHA.107.506022

Li, 2010, Neuroglobin protects neurons against oxidative stress in global ischemia, J. Cereb. Blood Flow Metab., 30, 1874, 10.1038/jcbfm.2010.90

Sun, 2003, Neuroglobin protects the brain from experimental stroke in vivo, Proc. Natl. Acad. Sci. USA, 100, 3497, 10.1073/pnas.0637726100

Cai, 2011, Tat-mediated delivery of neuroglobin protects against focal cerebral ischemia in mice, Exp. Neurol., 227, 224, 10.1016/j.expneurol.2010.11.009

Ord, 2013, Combined antiapoptotic and antioxidant approach to acute neuroprotection for stroke in hypertensive rats, J. Cereb. Blood Flow Metab., 33, 1215, 10.1038/jcbfm.2013.70

Hacke, 2008, Thrombolysis with alteplase 3 to 4.5 h after acute ischemic stroke, N. Engl. J. Med., 359, 1317, 10.1056/NEJMoa0804656

Liu, 2004, Tissue plasminogen activator neurovascular toxicity is controlled by activated protein c, Nat. Med., 10, 1379, 10.1038/nm1122

Baker, 2007, Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia, Proc. Natl. Acad. Sci. USA, 104, 3597, 10.1073/pnas.0611112104

Asahi, 2000, Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats, J. Cereb. Blood Flow Metab., 20, 452, 10.1097/00004647-200003000-00002

Barth, 1996, Combination therapy with MK-801 and alpha-phenyl-tert-butyl-nitrone enhances protection against ischemic neuronal damage in organotypic hippocampal slice cultures, Exp. Neurol., 141, 330, 10.1006/exnr.1996.0168

Deguchi, 2012, Modifying neurorepair and neuroregenerative factors with TPA and edaravone after transient middle cerebral artery occlusion in rat brain, Brain Res., 1436, 168, 10.1016/j.brainres.2011.12.016

David, 2012, Prothrombolytic action of normobaric oxygen given alone or in combination with recombinant tissue-plasminogen activator in a rat model of thromboembolic stroke, J. Appl. Physiol., 112, 2068, 10.1152/japplphysiol.00092.2012

Hungerhuber, 1999, Neuroprotective efficacy of combination therapy with two different antioxidants in rats subjected to transient focal ischemia, Brain Res., 816, 471, 10.1016/S0006-8993(98)01197-4

Macleod, 2012, Evaluation of combination therapy in animal models of cerebral ischemia, J. Cereb. Blood Flow Metab., 32, 585, 10.1038/jcbfm.2011.203

Dirnagl, 2006, Bench to bedside: The quest for quality in experimental stroke research, J. Cereb. Blood Flow Metab., 26, 1465, 10.1038/sj.jcbfm.9600298

Stroke Therapy Academic Industry Roundtable (STAIR) (1999). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke, 30, 2752–2758.

Fisher, 2009, Update of the stroke therapy academic industry roundtable preclinical recommendations, Stroke, 40, 2244, 10.1161/STROKEAHA.108.541128

Macleod, 2006, 1026 Experimental treatments in acute stroke, Ann. Neurol., 59, 467

Sena, 2007, How can we improve the pre-clinical development of drugs for stroke?, Trends Neurosci., 30, 433, 10.1016/j.tins.2007.06.009

Donnan, 2009, Scope of preclinical testing versus quality control within experiments, Stroke, 40, e497

Macleod, 2009, Good laboratory practice: Preventing introduction of bias at the bench, Stroke, 40, e50, 10.1161/STROKEAHA.108.525386

Kilkenny, 2010, Improving bioscience research reporting: The arrive guidelines for reporting animal research, PLoS Biol., 8, e1000412, 10.1371/journal.pbio.1000412

Dirnagl, 2013, A concerted appeal for international cooperation in preclinical stroke research, Stroke, 44, 1754, 10.1161/STROKEAHA.113.000734