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Targeting Oxidative Stress in Stroke

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Neuroprotective Therapy for Stroke and Ischemic Disease

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced under physiological conditions as innocent by-products and serve as useful redox signalling molecules. An advanced set of endogenous antioxidants safely handle these reactive species, which allows for them to be utilized by our cells and tissues. In many diseases, including ischaemic stroke, this fine balance is shifted so that our antioxidants are outnumbered by ROS and RNS; this results in oxidative stress, which can lead to toxicity and cell death with severe and potentially lethal consequences for the individual. Oxidative stress plays a crucial and central role in the pathophysiological cascade responsible for brain damage following a stroke by mediating severe toxicity in the acute phase and initiating and contributing to late-stage apoptosis and inflammation. This review will describe the chemistry, biochemical sources, and harmful effects of ROS/RNS in order to provide insight into the diverse and complex elements of oxidative stress. Then, oxidative stress’ relationship to ischaemic stroke will be addressed, with a focus on the biochemical mechanisms that lead to neurotoxicity. Pharmacological strategies to inhibit oxidative stress in cerebral ischaemia are discussed, including examples that cover past and present efforts. Three potential drug targets against oxidative stress and ischaemic stroke are highlighted, namely PSD-95, NADPH oxidase, and Keap1, and the potential of multi-target drug discovery in relation to ischaemic stroke is outlined.

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Abbreviations

AIF:

Apoptosis-inducing factor

AKBA:

Acetyl-11-keto-β-boswellic acid

AMPA:

α-Amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid

Apaf-1:

Apoptotic protease-activating factor-1

ARE:

Antioxidant response element

BBB:

Blood-brain barrier

cGMP:

Cyclic guanosine 3′,5′-monophosphate

COPD:

Chronic obstructive pulmonary disease

COX-2:

Cyclooxygenase-2

CPP:

Cell-penetrating peptide

CREB:

cAMP response element-binding protein

CSD:

Cortical spreading depression

DC:

Direct current

DMF:

Dimethyl fumarate

ENACT:

Evaluating neuroprotection in aneurysm coiling therapy

eNOS:

Endothelial nitric oxide synthase

FAD:

Flavin adenine dinucleotide

FADH2 :

Flavin adenine dinucleotide (reduced)

FBDD:

Fragment-based drug discovery

FMN:

Flavin mononucleotide

GPx:

Glutathione peroxidases

GST:

Glutathione S-transferase

HCAR2:

Hydroxycarboxylic acid receptor 2

HNE:

4-Hydroxy-2,3-nonenal

HO-1:

Heme oxygenase 1

HTS:

High-throughput screening

ICH:

Intracerebral haemorrhage

iNOS:

Inductive nitric oxide synthase

Keap1:

Kelch-like ECH-associated protein 1

l-NAME:

l-N G-nitroarginine methyl ester

l-NNA:

l-N G-nitroarginine

LTP:

Long-term potentiation

MMF:

Monomethyl fumarate

MOMP:

Mitochondrial outer membrane permeabilization

MPT:

Mitochondrial permeability transition

MPTP:

Mitochondrial permeability transition pore

NADH:

Nicotine adenine dinucleotide (reduced)

NADPH:

Nicotinamide adenine dinucleotide phosphate (reduced)

NMDA:

N-methyl-d-aspartate

nNOS:

Neuronal nitric oxide synthase

NOX:

NADPH oxidase (catalytical subunit)

NQO1:

NAD(P)H dehydrogenase (quinone) 1

Nrf2:

Nuclear erythroid-related factor 2

8-OH-dG:

8-Hydroxy-deoxy-guanidine

8-oxodG:

8-Oxo-2′-deoxyguanosine

PARP:

Poly (ADP-ribose) polymerase

PBN:

α-Phenyl-N-tert-butyl nitrone

PDZ:

PSD-95/Discs-large/ZO-1

PI3K:

Phosphatidylinositol-3-kinase

PKC:

Protein kinase C

PLA2 :

Phospholipase A2

PLC:

Phospholipase C

pMCAO:

Permanent middle cerebral artery occlusion

PSD-95:

Postsynaptic density protein-95

RET:

Reverse electron transport

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

RSCEM:

Rabbit small clot embolic stroke model

rtPA:

Recombinant tissue-plasminogen activator

RyR1:

Ryanodine receptor Ca2+ channel

SDH:

Succinate dehydrogenase

SOD:

Superoxide dismutase

STAIR:

Stroke therapy academic industry roundtable

STAZN:

Stilbazulenyl nitrone

tBHQ:

tert-butylhydroquinone

TCA:

Tricarboxylic acid

tMCAO:

Transient middle cerebral artery occlusion

TRPM7:

Transient receptor potential cation channel M7

XO:

Xanthine oxidase

References

  1. Li XY, Fang P, Mai JT, Choi ET, Wang H, Yang XF (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6

    Google Scholar 

  2. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24(10):R453–R462

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Novo E, Parola M (2008) Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 1(1):5

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. D’Autreaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8(10):813–824

    Article  PubMed  CAS  Google Scholar 

  5. Winterbourn CC (2008) Reconciling the chemistry and biology of reactive oxygen species. Nat Chem Biol 4(5):278–286

    Article  CAS  PubMed  Google Scholar 

  6. Kalogeris T, Bao Y, Korthuis RJ (2014) Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol 2:702–714

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Rhee SG (2006) Cell signaling. H2O2, a necessary evil for cell signaling. Science 312(5782):1882–1883

    Article  PubMed  Google Scholar 

  8. Rodrigo R, Fernandez-Gajardo R, Gutierrez R, Matamala JM, Carrasco R, Miranda-Merchak A et al (2013) Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol Disord Drug Targets 12(5):698–714

    Article  CAS  PubMed  Google Scholar 

  9. Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7(1):65–74

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87(1):315–424

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Imlay JA (2013) The molecular mechanisms and physiological consequences of oxidative stress: lessons from a model bacterium. Nat Rev Microbiol 11(7):443–454

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Naqui A, Chance B, Cadenas E (1986) Reactive oxygen intermediates in biochemistry. Annu Rev Biochem 55:137–166

    Article  CAS  PubMed  Google Scholar 

  13. Cadenas E, Davies KJ (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med 29(3-4):222–230

    Article  CAS  PubMed  Google Scholar 

  14. Walling C (1975) Fentons reagent revisited. Acc Chem Res 8(4):125–131

    Article  CAS  Google Scholar 

  15. Thomas C, Mackey MM, Diaz AA, Cox DP (2009) Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation. Redox Rep 14(3):102–108

    Article  CAS  PubMed  Google Scholar 

  16. Bidmon HJ, Emde B, Kowalski T, Schmitt M, Mayer B, Kato K et al (2001) Nitric oxide synthase-I containing cortical interneurons co-express antioxidative enzymes and anti-apoptotic Bcl-2 following focal ischemia: evidence for direct and indirect mechanisms towards their resistance to neuropathology. J Chem Neuroanat 22(3):167–184

    Article  CAS  PubMed  Google Scholar 

  17. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552(Pt 2):335–344

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Han D, Antunes F, Canali R, Rettori D, Cadenas E (2003) Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem 278(8):5557–5563

    Article  CAS  PubMed  Google Scholar 

  19. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Phys Rev 87(1):245–313

    CAS  Google Scholar 

  20. Brown DI, Griendling KK (2009) Nox proteins in signal transduction. Free Radic Biol Med 47(9):1239–1253

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Lienhart WD, Gudipati V, Macheroux P (2013) The human flavoproteome. Arch Biochem Biophys 535(2):150–162

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Imlay JA (2003) Pathways of oxidative damage. Annu Rev Microbiol 57:395–418

    Article  CAS  PubMed  Google Scholar 

  23. Messner KR, Imlay JA (2002) Mechanism of superoxide and hydrogen peroxide formation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase. J Biol Chem 277(45):42563–42571

    Article  CAS  PubMed  Google Scholar 

  24. Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (2007) Trends in oxidative aging theories. Free Radic Biol Med 43(4):477–503

    Article  CAS  PubMed  Google Scholar 

  25. Phung CD, Ezieme JA, Turrens JF (1994) Hydrogen-peroxide metabolism in skeletal-muscle mitochondria. Arch Biochem Biophys 315(2):479–482

    Article  CAS  PubMed  Google Scholar 

  26. Radi R, Turrens JF, Chang LY, Bush KM, Crapo JD, Freeman BA (1991) Detection of catalase in rat heart mitochondria. J Biol Chem 266(32):22028–22034

    CAS  PubMed  Google Scholar 

  27. Berndt C, Lillig CH, Holmgren A (2007) Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: implications for diseases in the cardiovascular system. Am J Physiol Heart Circ Physiol 292(3):H1227–H1236

    Article  CAS  PubMed  Google Scholar 

  28. Arnér ES, Holmgren A (2000) Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 267(20):6102–6109

    Article  PubMed  Google Scholar 

  29. Wood ZA, Schroder E, Robin Harris J, Poole LB (2003) Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sci 28(1):32–40

    Article  CAS  PubMed  Google Scholar 

  30. Maxwell SRJ, Thomason H, Sandler D, Leguen C, Baxter MA, Thorpe GHG et al (1997) Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. Eur J Clin Invest 27(6):484–490

    Article  CAS  PubMed  Google Scholar 

  31. Gilgun-Sherki Y, Melamed E, Offen D (2004) The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol 251(3):261–268

    Article  CAS  PubMed  Google Scholar 

  32. Guzik TJ, West NE, Pillai R, Taggart DP, Channon KM (2002) Nitric oxide modulates superoxide release and peroxynitrite formation in human blood vessels. Hypertension 39(6):1088–1094

    Article  CAS  PubMed  Google Scholar 

  33. Madamanchi NR, Runge MS (2007) Mitochondrial dysfunction in atherosclerosis. Circ Res 100(4):460–473

    Article  CAS  PubMed  Google Scholar 

  34. Grzelak A, Soszynski M, Bartosz G (2000) Inactivation of antioxidant enzymes by peroxynitrite. Scand J Clin Lab Invest 60(4):253–258

    Article  CAS  PubMed  Google Scholar 

  35. Peluffo G, Radi R (2007) Biochemistry of protein tyrosine nitration in cardiovascular pathology. Cardiovasc Res 75(2):291–302

    Article  CAS  PubMed  Google Scholar 

  36. West AP, Shadel GS, Ghosh S (2011) Mitochondria in innate immune responses. Nat Rev Immunol 11(6):389–402

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Valavanidis A, Vlachogianni T, Fiotakis K, Loridas S (2013) Pulmonary oxidative stress, inflammation and cancer: respirable particulate matter, fibrous dusts and ozone as major causes of lung carcinogenesis through reactive oxygen species mechanisms. Int J Environ Res Public Health 10(9):3886–3907

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8(9):741–752

    Article  CAS  PubMed  Google Scholar 

  39. Dalleau S, Baradat M, Gueraud F, Huc L (2013) Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance. Cell Death Differ 20(12):1615–1630

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Bernardi P, Petronilli V, Di Lisa F, Forte M (2001) A mitochondrial perspective on cell death. Trends Biochem Sci 26(2):112–117

    Article  CAS  PubMed  Google Scholar 

  41. Murphy AN, Fiskum G, Beal MF (1999) Mitochondria in neurodegeneration: bioenergetic function in cell life and death. J Cereb Blood Flow Metab 19(3):231–245

    Article  CAS  PubMed  Google Scholar 

  42. Sims NR, Muyderman H (2010) Mitochondria, oxidative metabolism and cell death in stroke. Biochem Biophys Acta 1802(1):80–91

    CAS  PubMed  Google Scholar 

  43. Scherz-Shouval R, Elazar Z (2007) ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 17(9):422–427

    Article  CAS  PubMed  Google Scholar 

  44. Hampton MB, Orrenius S (1997) Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis. FEBS Lett 414(3):552–556

    Article  CAS  PubMed  Google Scholar 

  45. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67(2):181–198

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Virag L, Robaszkiewicz A, Rodriguez-Vargas JM, Oliver FJ (2013) Poly(ADP-ribose) signaling in cell death. Mol Aspects Med 34(6):1153–1167

    Article  CAS  PubMed  Google Scholar 

  48. Ekblad T, Camaioni E, Schuler H, Macchiarulo A (2013) PARP inhibitors: polypharmacology versus selective inhibition. FEBS J 280(15):3563–3575

    Article  CAS  PubMed  Google Scholar 

  49. Lai TW, Zhang S, Wang YT (2014) Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115:157–188

    Article  CAS  PubMed  Google Scholar 

  50. Kaminski MM, Roth D, Krammer PH, Gulow K (2013) Mitochondria as oxidative signaling organelles in T-cell activation: physiological role and pathological implications. Arch Immunol Ther Exp (Warsz) 61(5):367–384

    Article  CAS  Google Scholar 

  51. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA et al (2014) Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 383(9913):245–254

    Article  PubMed Central  PubMed  Google Scholar 

  52. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V et al (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(9859):2095–2128

    Article  PubMed  Google Scholar 

  53. World Health Organization (WHO). The top ten causes of death. http://www.who.int/mediacentre/factsheets/fs310/en/ (Updated May 2014).

  54. Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  55. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M et al (2015) Heart disease and stroke statistics—2015 update, a report from the American Heart Association. Circulation 131(4):E29–E322

    Article  PubMed  Google Scholar 

  56. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22(9):391–397

    Article  CAS  PubMed  Google Scholar 

  57. Iadecola C, Anrather J (2011) Stroke research at a crossroad: asking the brain for directions. Nat Neurosci 14(11):1363–1368

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Stankowski JN, Gupta R (2011) Therapeutic targets for neuroprotection in acute ischemic stroke: lost in translation? Antioxid Redox Signal 14(10):1841–1851

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Sutherland BA, Minnerup J, Balami JS, Arba F, Buchan AM, Kleinschnitz C (2012) Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke 7(5):407–418

    Article  PubMed  Google Scholar 

  60. Furlan AJ (2015) Endovascular therapy for stroke—it’s about time. N Engl J Med 372(24):2347–2349

    Article  PubMed  Google Scholar 

  61. Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM et al (2015) Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 372(24):2285–2295

    Article  CAS  PubMed  Google Scholar 

  62. Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4(5):399–415

    Article  CAS  PubMed  Google Scholar 

  63. Aarts MM, Tymianski M (2003) Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors. Biochem Pharmacol 66(6):877–886

    Article  CAS  PubMed  Google Scholar 

  64. Nicholls DG (2008) Oxidative stress and energy crises in neuronal dysfunction. Ann N Y Acad Sci 1147:53–60

    Article  CAS  PubMed  Google Scholar 

  65. Choi DW, Rothman SM (1990) The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 13:171–182

    Article  CAS  PubMed  Google Scholar 

  66. Besancon E, Guo SZ, Lok J, Tymianski M, Lo EH (2008) Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke. Trends Pharmacol Sci 29(5):268–275

    Article  CAS  PubMed  Google Scholar 

  67. Tymianski M (2011) Emerging mechanisms of disrupted cellular signaling in brain ischemia. Nat Neurosci 14(11):1369–1373

    Article  CAS  PubMed  Google Scholar 

  68. Adibhatla RM, Hatcher JF, Dempsey RJ (2003) Phospholipase A2, hydroxyl radicals, and lipid peroxidation in transient cerebral ischemia. Antioxid Redox Signal 5(5):647–654

    Article  CAS  PubMed  Google Scholar 

  69. Adibhatla RM, Hatcher JF (2010) Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 12(1):125–169

    Article  CAS  PubMed  Google Scholar 

  70. Li WJ, Wu SS, Ahmad M, Jiang JF, Liu H, Nagayama T et al (2010) The cyclooxygenase site, but not the peroxidase site of cyclooxygenase-2 is required for neurotoxicity in hypoxic and ischemic injury. J Neurochem 113(4):965–977

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Yuan J (2009) Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis 14(4):469–477

    Article  PubMed Central  PubMed  Google Scholar 

  72. Abramov AY, Scorziello A, Duchen MR (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 27(5):1129–1138

    Article  CAS  PubMed  Google Scholar 

  73. Nicholls DG (2004) Mitochondrial dysfunction and glutamate excitotoxicity studied in primary neuronal cultures. Curr Mol Med 4(2):149–177

    Article  CAS  PubMed  Google Scholar 

  74. Fiskum G, Murphy AN, Beal MF (1999) Mitochondria in neurodegeneration: acute ischemia and chronic neurodegenerative diseases. J Cereb Blood Flow Metab 19(4):351–369

    Article  CAS  PubMed  Google Scholar 

  75. Leung AWC, Halestrap AP (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777(7-8):946–952

    Article  CAS  PubMed  Google Scholar 

  76. Drummond GR, Selemidis S, Griendling KK, Sobey CG (2011) Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov 10(6):453–471

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M et al. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol. 2010;8(9).

    Google Scholar 

  78. Kahles T, Brandes RP (2013) Which NADPH oxidase isoform is relevant for ischemic stroke? The case for Nox 2. Antioxid Redox Signal 18(12):1400–1417

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Dikalov S (2011) Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med 51(7):1289–1301

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Block K, Gorin Y, Abboud HE (2009) Subcellular localization of Nox4 and regulation in diabetes. Proc Natl Acad Sci U S A 106(34):14385–14390

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Brennan AM, Suh SW, Won SJ, Narasimhan P, Kauppinen TM, Lee H et al (2009) NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci 12(7):857–863

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Girouard H, Wang G, Gallo EF, Anrather J, Zhou P, Pickel VM et al (2009) NMDA receptor activation increases free radical production through nitric oxide and NOX2. J Neurosci 29(8):2545–2552

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Nishino T, Okamoto K, Kawaguchi Y, Hori H, Matsumura T, Eger BT et al (2005) Mechanism of the conversion of xanthine dehydrogenase to xanthine oxidase: identification of the two cysteine disulfide bonds and crystal structure of a non-convertible rat liver xanthine dehydrogenase mutant. J Biol Chem 280(26):24888–24894

    Article  CAS  PubMed  Google Scholar 

  84. Pacher P, Nivorozhkin A, Szabo C (2006) Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 58(1):87–114

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Bonini MG, Miyamoto S, Di Mascio P, Augusto O (2004) Production of the carbonate radical anion during xanthine oxidase turnover in the presence of bicarbonate. J Biol Chem 279(50):51836–51843

    Article  CAS  PubMed  Google Scholar 

  86. Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY, Robb EL et al (2014) Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515(7527):431–435

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Forstermann U (2010) Nitric oxide and oxidative stress in vascular disease. Pflugers Arch 459(6):923–939

    Article  PubMed  CAS  Google Scholar 

  88. Endres M, Laufs U, Liao JK, Moskowitz MA (2004) Targeting eNOS for stroke protection. Trends Neurosci 27(5):283–289

    Article  CAS  PubMed  Google Scholar 

  89. Parathath SR, Gravanis I, Tsirka SE (2007) Nitric oxide synthase isoforms undertake unique roles during excitotoxicity. Stroke 38(6):1938–1945

    Article  CAS  PubMed  Google Scholar 

  90. Iadecola C (1997) Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci 20(3):132–139

    Article  CAS  PubMed  Google Scholar 

  91. Lafon-Cazal M, Pietri S, Culcasi M, Bockaert J (1993) NMDA-dependent superoxide production and neurotoxicity. Nature 364(6437):535–537

    Article  CAS  PubMed  Google Scholar 

  92. Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M (1999) Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284(5421):1845–1848

    Article  CAS  PubMed  Google Scholar 

  93. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW et al (2002) Treatment of ischemic brain damage by perturbing NMDA receptor—PSD-95 protein interactions. Science 298(5594):846–850

    Article  CAS  PubMed  Google Scholar 

  94. Aarts MM, Tymianski M (2004) Molecular mechanisms underlying specificity of excitotoxic signaling in neurons. Curr Mol Med 4(2):137–147

    Article  CAS  PubMed  Google Scholar 

  95. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci U S A 88(14):6368–6371

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Nowicki JP, Duval D, Poignet H, Scatton B (1991) Nitric oxide mediates neuronal death after focal cerebral ischemia in the mouse. Eur J Pharmacol 204(3):339–340

    Article  CAS  PubMed  Google Scholar 

  97. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA (1994) Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265(5180):1883–1885

    Article  CAS  PubMed  Google Scholar 

  98. Dawson VL, Dawson TM, Bartley DA, Uhl GR, Snyder SH (1993) Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. J Neurosci 13(6):2651–2661

    CAS  PubMed  Google Scholar 

  99. Dawson VL, Kizushi VM, Huang PL, Snyder SH, Dawson TM (1996) Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. J Neurosci 16(8):2479–2487

    CAS  PubMed  Google Scholar 

  100. Xia Y, Dawson VL, Dawson TM, Snyder SH, Zweier JL (1996) Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci U S A 93(13):6770–6774

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Lipton SA, Choi YB, Pan ZH, Lei SZ, Chen HS, Sucher NJ et al (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364(6438):626–632

    Article  CAS  PubMed  Google Scholar 

  102. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 87(4):1620–1624

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W et al (2003) A key role for TRPM7 channels in anoxic neuronal death. Cell 115(7):863–877

    Article  CAS  PubMed  Google Scholar 

  104. Szabo C (1996) DNA strand breakage and activation of poly-ADP ribosyltransferase: a cytotoxic pathway triggered by peroxynitrite. Free Radic Biol Med 21(6):855–869

    Article  CAS  PubMed  Google Scholar 

  105. Chiarugi A (2005) Poly (ADP-ribosyl)ation and stroke. Pharmacol Res 52(1):15–24

    Article  CAS  PubMed  Google Scholar 

  106. Mandir AS, Poitras MF, Berliner AR, Herring WJ, Guastella DB, Feldman A et al (2000) NMDA but not non-NMDA excitotoxicity is mediated by poly(ADP-ribose) polymerase. J Neurosci 20(21):8005–8011

    CAS  PubMed  Google Scholar 

  107. Zaobornyj T, Ghafourifar P (2012) Strategic localization of heart mitochondrial NOS: a review of the evidence. Am J Physiol Heart Circ Physiol 303(11):H1283–H1293

    Article  CAS  PubMed  Google Scholar 

  108. Ghafourifar P, Cadenas E (2005) Mitochondrial nitric oxide synthase. Trends Pharmacol Sci 26(4):190–195

    Article  CAS  PubMed  Google Scholar 

  109. Brookes PS (2004) Mitochondrial nitric oxide synthase. Mitochondrion 3(4):187–204

    Article  CAS  PubMed  Google Scholar 

  110. Dalkara T, Endres M, Moskowitz MA (1998) Mechanisms of NO neurotoxicity. Prog Brain Res 118:231–239

    Article  CAS  PubMed  Google Scholar 

  111. Lynch RE, Fridovich I (1978) Permeation of the erythrocyte stroma by superoxide radical. J Biol Chem 253(13):4697–4699

    CAS  PubMed  Google Scholar 

  112. Fisher AB (2009) Redox signaling across cell membranes. Antioxid Redox Signal 11(6):1349–1356

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. Macfadyen AJ, Reiter C, Zhuang YX, Beckman JS (1999) A novel superoxide dismutase-based trap for peroxynitrite used to detect entry of peroxynitrite into erythrocyte ghosts. Chem Res Toxicol 12(3):223–229

    Article  CAS  PubMed  Google Scholar 

  114. Denicola A, Souza JM, Radi R (1998) Diffusion of peroxynitrite across erythrocyte membranes. Proc Natl Acad Sci U S A 95(7):3566–3571

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Marla SS, Lee J, Groves JT (1997) Peroxynitrite rapidly permeates phospholipid membranes. Proc Natl Acad Sci U S A 94(26):14243–14248

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  116. Turko IV, Murad F (2002) Protein nitration in cardiovascular diseases. Pharmacol Rev 54(4):619–634

    Article  CAS  PubMed  Google Scholar 

  117. Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79(4):1431–1568

    CAS  PubMed  Google Scholar 

  118. Wong CHY, Crack PJ (2008) Modulation of neuro-inflammation and vascular response by oxidative stress following cerebral ischemia-reperfusion injury. Curr Med Chem 15(1):1–14

    Article  CAS  PubMed  Google Scholar 

  119. Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62(6):649–671

    Article  CAS  PubMed  Google Scholar 

  120. Granger DN (1988) Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol 255(6 Pt 2):H1269–H1275

    CAS  PubMed  Google Scholar 

  121. Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21(1):2–14

    Article  CAS  PubMed  Google Scholar 

  122. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333(24):1581–1587

    Article  Google Scholar 

  123. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC et al (2010) Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 375(9727):1695–1703

    Article  CAS  PubMed  Google Scholar 

  124. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E et al (2014) Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 384(9958):1929–1935

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D et al (2008) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359(13):1317–1329

    Article  CAS  PubMed  Google Scholar 

  126. Lapchak PA (2011) Emerging therapies: pleiotropic multi-target drugs to treat stroke victims. Transl Stroke Res 2(2):129–135

    Article  PubMed Central  PubMed  Google Scholar 

  127. Fonarow GC, Smith EE, Saver JL, Reeves MJ, Bhatt DL, Grau-Sepulveda MV et al (2011) Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation 123(7):750–758

    Article  CAS  PubMed  Google Scholar 

  128. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ et al (2015) A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 372(1):11–20

    Article  PubMed  CAS  Google Scholar 

  129. Cheng YD, Al-Khoury L, Zivin JA (2004) Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx 1(1):36–45

    Article  PubMed Central  PubMed  Google Scholar 

  130. Lapchak PA, Araujo DM, Song D, Wei J, Zivin JA (2002) Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke 33(5):1411–1415

    Article  CAS  PubMed  Google Scholar 

  131. Kahle MP, Bix GJ (2012) Successfully climbing the “STAIRs”: surmounting failed translation of experimental ischemic stroke treatments. Stroke Res Treat 2012:374098

    PubMed Central  PubMed  Google Scholar 

  132. Lapchak PA, Araujo DM (2007) Advances in ischemic stroke treatment: neuroprotective and combination therapies. Expert Opin Emerg Drugs 12(1):97–112

    Article  CAS  PubMed  Google Scholar 

  133. Garber K (2007) Stroke treatment-light at the end of the tunnel? Nat Biotechnol 25(8):838–840

    Article  CAS  PubMed  Google Scholar 

  134. Savitz SI, Fisher M (2007) Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials. Ann Neurol 61(5):396–402

    Article  CAS  PubMed  Google Scholar 

  135. Tymianski M (2013) Novel approaches to neuroprotection trials in acute ischemic stroke. Stroke 44(10):2942–2950

    Article  PubMed  Google Scholar 

  136. Tymianski M (2010) Can molecular and cellular neuroprotection be translated into therapies for patients? Yes, but not the way we tried it before. Stroke 41(10):S87–S90

    Article  PubMed  Google Scholar 

  137. Saver JL, Starkman S, Eckstein M, Stratton SJ, Pratt FD, Hamilton S et al (2015) Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med 372(6):528–536

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  138. Itrat A, Taqui A, Cerejo R, Briggs F, Cho SM, Organek N et al (2016) Telemedicine in prehospital stroke evaluation and thrombolysis: taking stroke treatment to the doorstep. JAMA Neurol 73(2):162–168

    Article  PubMed  Google Scholar 

  139. Ebinger M, Winter B, Wendt M, Weber JE, Waldschmidt C, Rozanski M et al (2014) Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA 311(16):1622–1631

    Article  CAS  PubMed  Google Scholar 

  140. O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW (2006) 1,026 experimental treatments in acute stroke. Ann Neurol 59(3):467–477

    Article  PubMed  CAS  Google Scholar 

  141. Dirnagl U (2006) Bench to bedside: the quest for quality in experimental stroke research. J Cereb Blood Flow Metab 26(12):1465–1478

    Article  PubMed  Google Scholar 

  142. Ginsberg MD (2008) Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 55(3):363–389

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Ginsberg MD (2009) Current status of neuroprotection for cerebral ischemia: synoptic overview. Stroke 40(3 Suppl):S111–S114

    Article  PubMed  Google Scholar 

  144. Moskowitz MA (2010) Brain protection maybe yes, maybe no. Stroke 41(10):S85–S86

    Article  PubMed  Google Scholar 

  145. Muir KW (2006) Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists. Curr Opin Pharmacol 6(1):53–60

    Article  CAS  PubMed  Google Scholar 

  146. Hoyte L, Barber PA, Buchan AM, Hill MD (2004) The rise and fall of NMDA antagonists for ischemic stroke. Curr Mol Med 4(2):131–136

    Article  CAS  PubMed  Google Scholar 

  147. Ikonomidou C, Turski L (2002) Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol 1(6):383–386

    Article  CAS  PubMed  Google Scholar 

  148. Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11(10):682–696

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  149. Papadia S, Hardingham GE (2007) The dichotomy of NMDA receptor signaling. Neuroscientist 13(6):572–579

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  150. Mehta SL, Manhas N, Raghubir R (2007) Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 54(1):34–66

    Article  CAS  PubMed  Google Scholar 

  151. Watts LT, Lloyd R, Garling RJ, Duong T (2013) Stroke neuroprotection: targeting mitochondria. Brain Sci 3(2):540–560

    Article  PubMed  Google Scholar 

  152. STAIR (1999) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30(12):2752–2758

    Article  Google Scholar 

  153. Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI et al (2009) Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 40(6):2244–2250

    Article  PubMed Central  PubMed  Google Scholar 

  154. Turner RJ, Jickling GC, Sharp FR (2011) Are underlying assumptions of current animal models of human stroke correct: from STAIRs to high hurdles? Transl Stroke Res 2(2):138–143

    Article  PubMed Central  PubMed  Google Scholar 

  155. Tymianski M. Neuroprotective therapies: preclinical reproducibility is only part of the problem. Sci Transl Med. 2015;7(299).

    Google Scholar 

  156. Llovera G, Hofmann K, Roth S, Salas-Perdomo A, Ferrer-Ferrer M, Perego C et al. Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia. Sci Transl Med. 2015;7(299):299ra121.

    Google Scholar 

  157. Cook DJ, Teves L, Tymianski M (2012) Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 483(7388):213–217

    Article  CAS  PubMed  Google Scholar 

  158. Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael ST (2010) Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468(7321):305–309

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  159. Lapchak PA (2010) Translational stroke research using a rabbit embolic stroke model: a correlative analysis hypothesis for novel therapy development. Transl Stroke Res 1(2):96–107

    Article  PubMed Central  PubMed  Google Scholar 

  160. Lapchak PA (2015) A cost-effective rabbit embolic stroke bioassay: insight into the development of acute ischemic stroke therapy. Transl Stroke Res 6(2):99–103

    Article  PubMed Central  PubMed  Google Scholar 

  161. Hill MD, Martin RH, Mikulis D, Wong JH, Silver FL, Terbrugge KG et al (2012) Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 11(11):942–950

    Article  CAS  PubMed  Google Scholar 

  162. Gilgun-Sherki Y, Rosenbaum Z, Melamed E, Offen D (2002) Antioxidant therapy in acute central nervous system injury: current state. Pharmacol Rev 54(2):271–284

    Article  CAS  PubMed  Google Scholar 

  163. Shirley R, Ord EN, Work LM (2014) Oxidative stress and the use of antioxidants in stroke. Antioxidants (Basel) 3(3):472–501

    Article  CAS  Google Scholar 

  164. Sena E, Wheble P, Sandercock P, Macleod M (2007) Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. Stroke 38(2):388–394

    Article  CAS  PubMed  Google Scholar 

  165. Parnham M, Sies H (2000) Ebselen: prospective therapy for cerebral ischaemia. Expert Opin Investig Drugs 9(3):607–619

    Article  CAS  PubMed  Google Scholar 

  166. Sakurai T, Kanayama M, Shibata T, Itoh K, Kobayashi A, Yamamoto M et al (2006) Ebselen, a seleno-organic antioxidant, as an electrophile. Chem Res Toxicol 19(9):1196–1204

    Article  CAS  PubMed  Google Scholar 

  167. Lapchak PA, Zivin JA (2003) Ebselen, a seleno-organic antioxidant, is neuroprotective after embolic strokes in rabbits: synergism with low-dose tissue plasminogen activator. Stroke 34(8):2013–2018

    Article  CAS  PubMed  Google Scholar 

  168. Kuroda S, Tsuchidate R, Smith ML, Maples KR, Siesjo BK (1999) Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 19(7):778–787

    Article  CAS  PubMed  Google Scholar 

  169. Marshall JWB, Cummings RM, Bowes LJ, Ridley RM, Green AR (2003) Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke 34(9):2228–2233

    Article  CAS  PubMed  Google Scholar 

  170. Marshall JW, Duffin KJ, Green AR, Ridley RM (2001) NXY-059, a free radical-trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species. Stroke 32(1):190–198

    Article  CAS  PubMed  Google Scholar 

  171. Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener H et al (2006) NXY-059 for acute ischemic stroke. N Engl J Med 354(6):588–600

    Article  CAS  PubMed  Google Scholar 

  172. Lees KR, Davalos A, Davis SM, Diener HC, Grotta J, Lyden P et al (2006) Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial. Stroke 37(12):2970–2978

    Article  PubMed  Google Scholar 

  173. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM et al (2007) NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 357(6):562–571

    Article  CAS  PubMed  Google Scholar 

  174. Savitz SI (2007) A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp Neurol 205(1):20–25

    Article  CAS  PubMed  Google Scholar 

  175. Macleod MR, van der Worp HB, Sena ES, Howells DW, Dirnagl U, Donnan GA (2008) Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke 39(10):2824–2829

    Article  PubMed  Google Scholar 

  176. Bath PMW, Gray LJ, Bath AJG, Buchan A, Miyata T, Green AR et al (2009) Effects of NXY-059 in experimental stroke: an individual animal meta-analysis. Br J Pharmacol 157(7):1157–1171

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  177. Becker DA, Ley JJ, Echegoyen L, Alvarado R (2002) Stilbazulenyl nitrone (STAZN): a nitronyl-substituted hydrocarbon with the potency of classical phenolic chain-breaking antioxidants. J Am Chem Soc 124(17):4678–4684

    Article  CAS  PubMed  Google Scholar 

  178. Lapchak PA, Schubert DR, Maher PA (2011) De-risking of stilbazulenyl nitrone (STAZN), a lipophilic nitrone to treat stroke using a unique panel of in vitro assays. Transl Stroke Res 2(2):209–217

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  179. Maples KR, Ma F, Zhang YK (2001) Comparison of the radical trapping ability of PBN, S-PPBN and NXY-059. Free Radic Res 34(4):417–426

    Article  CAS  PubMed  Google Scholar 

  180. Zhang N, Komine-Kobayashi M, Tanaka R, Liu MZ, Mizuno Y, Urabe T (2005) Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke 36(10):2220–2225

    Article  CAS  PubMed  Google Scholar 

  181. Nakajima H, Kakui N, Ohkuma K, Ishikawa M, Hasegawa T (2005) A newly synthesized poly(ADP-ribose) polymerase inhibitor, DR2313 [2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidine-4-one]: pharmacological profiles, neuroprotective effects, and therapeutic time window in cerebral ischemia in rats. J Pharmacol Exp Ther 312(2):472–481

    Article  CAS  PubMed  Google Scholar 

  182. Lapchak PA, Zivin JA (2009) The lipophilic multifunctional antioxidant edaravone (radicut) improves behavior following embolic strokes in rabbits: a combination therapy study with tissue plasminogen activator. Exp Neurol 215(1):95–100

    Article  CAS  PubMed  Google Scholar 

  183. Otomo E, Tohgi H, Kogure K, Hirai S, Takakura K, Terashi A et al (2003) Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction—randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis 15(3):222–229

    Article  CAS  Google Scholar 

  184. Nakase T, Yoshioka S, Suzuki A (2011) Free radical scavenger, edaravone, reduces the lesion size of lacunar infarction in human brain ischemic stroke. BMC Neurol 11:39

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  185. Inatomi Y, Takita T, Yonehara T, Fujioka S, Hashimoto Y, Hirano T et al (2006) Efficacy of edaravone in cardioembolic stroke. Intern Med 45(5):253–257

    Article  PubMed  Google Scholar 

  186. Lapchak PA (2010) A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy? Expert Opin Pharmacother 11(10):1753–1763

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  187. Feng SJ, Yang QW, Liu M, Li WZ, Yuan WM, Zhang SH et al (2011) Edaravone for acute ischaemic stroke. Cochrane Database Syst Rev 12, CD007230

    Google Scholar 

  188. Wingler K, Hermans JJ, Schiffers P, Moens A, Paul M, Schmidt HH (2011) NOX1, 2, 4, 5: counting out oxidative stress. Br J Pharmacol 164(3):866–883

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  189. Bath PM, Willmot M, Leonardi-Bee J, Bath FJ (2002) Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke. Cochrane Database Syst Rev 4, CD000398

    Google Scholar 

  190. Terpolilli NA, Moskowitz MA, Plesnila N (2012) Nitric oxide: considerations for the treatment of ischemic stroke. J Cereb Blood Flow Metab 32(7):1332–1346

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  191. Willmot M, Gibson C, Gray L, Murphy S, Bath P (2005) Nitric oxide synthase inhibitors in experimental ischemic stroke and their effects on infarct size and cerebral blood flow: a systematic review. Free Radic Biol Med 39(3):412–425

    Article  CAS  PubMed  Google Scholar 

  192. Parmentier S, Bohme GA, Lerouet D, Damour D, Stutzmann JM, Margaill I et al (1999) Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury. Br J Pharmacol 127(2):546–552

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  193. Chabrier PE, Auguet M, Spinnewyn B, Auvin S, Cornet S, Demerle-Pallardy C et al (1999) BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: A promising neuroprotective strategy. Proc Natl Acad Sci U S A 96(19):10824–10829

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  194. Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357:593–615

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  195. Lin Y, Phillis JW (1992) Deoxycoformycin and oxypurinol—protection against focal ischemic brain injury in the rat. Brain Res 571(2):272–280

    Article  CAS  PubMed  Google Scholar 

  196. Arai T, Mori H, Ishii H, Adachi T, Endo N, Makino K et al (1998) Oxypurinol, a xanthine oxidase inhibitor and a superoxide scavenger, did not attenuate ischemic neuronal damage in gerbils. Life Sci 63(7):l107–l112

    Article  Google Scholar 

  197. Nakashima M, Niwa M, Iwai T, Uematsu T (1999) Involvement of free radicals in cerebral vascular reperfusion injury evaluated in a transient focal cerebral ischemia model of rat. Free Radic Biol Med 26(5-6):722–729

    Article  CAS  PubMed  Google Scholar 

  198. Van Bel F, Shadid M, Moison RMW, Dorrepaal CA, Fontijn J, Monteiro L et al (1998) Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics 101(2):185–193

    Article  PubMed  Google Scholar 

  199. Higgins P, Ferguson LD, Walters MR (2011) Xanthine oxidase inhibition for the treatment of stroke disease: a novel therapeutic approach. Expert Rev Cardiovasc Ther 9(4):399–401

    Article  CAS  PubMed  Google Scholar 

  200. Christopherson KS, Hillier BJ, Lim WA, Bredt DS (1999) PSD-95 assembles a ternary complex with the N-methyl-d-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J Biol Chem 274(39):27467–27473

    Article  CAS  PubMed  Google Scholar 

  201. Sun HS, Doucette TA, Liu Y, Fang Y, Teves L, Aarts M et al (2008) Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke 39(9):2544–2553

    Article  CAS  PubMed  Google Scholar 

  202. Soriano FX, Martel MA, Papadia S, Vaslin A, Baxter P, Rickman C et al (2008) Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand. J Neurosci 28(42):10696–10710

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  203. Bratane BT, Cui H, Cook DJ, Bouley J, Tymianski M, Fisher M (2011) Neuroprotection by freezing ischemic penumbra evolution without cerebral blood flow augmentation with a postsynaptic density-95 protein inhibitor. Stroke 42(11):3265–3270

    Article  CAS  PubMed  Google Scholar 

  204. Bell KF, Bent RJ, Meese-Tamuri S, Ali A, Forder JP, Aarts MM (2013) Calmodulin kinase IV-dependent CREB activation is required for neuroprotection via NMDA receptor-PSD95 disruption. J Neurochem 126(2):274–287

    Article  CAS  PubMed  Google Scholar 

  205. Teves LM, Cui H, Tymianski M (2016) Efficacy of the PSD95 inhibitor Tat-NR2B9c in mice requires dose translation between species. J Cereb Blood Flow Metab 36(3):555–561

    Article  CAS  PubMed  Google Scholar 

  206. Cook DJ, Teves L, Tymianski M. A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic nonhuman primates. Sci Transl Med. 2012;4(154):154ra33.

    Google Scholar 

  207. Bach A, Chi CN, Olsen TB, Pedersen SW, Røder MU, Pang GF et al (2008) Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-d-aspartate receptor interaction. J Med Chem 51(20):6450–6459

    Article  CAS  PubMed  Google Scholar 

  208. Bach A, Clausen BH, Møller M, Vestergaard B, Chi CN, Round A et al (2012) A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. Proc Natl Acad Sci U S A 109(9):3317–3322

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  209. Cui H, Hayashi A, Sun HS, Belmares MP, Cobey C, Phan T et al (2007) PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. J Neurosci 27(37):9901–9915

    Article  CAS  PubMed  Google Scholar 

  210. Tymianski M, Garman JD. Co-administration of an agent linked to an internalization peptide with an anti-inflammatory. 2011; Patent US 8,080,518 B2.

    Google Scholar 

  211. Sarko D, Beijer B, Garcia Boy R, Nothelfer EM, Leotta K, Eisenhut M et al (2010) The pharmacokinetics of cell-penetrating peptides. Mol Pharm 7(6):2224–2231

    Article  CAS  PubMed  Google Scholar 

  212. Bach A, Pedersen TB, Strømgaard K (2016) Design and synthesis of triazole-based peptidomimetics of a PSD-95 PDZ domain inhibitor. Med Chem Commun 7(3):531–536

    Article  CAS  Google Scholar 

  213. Chi CN, Bach A, Strømgaard K, Gianni S, Jemth P (2012) Ligand binding by PDZ domains. Biofactors 38(5):338–348

    Article  CAS  PubMed  Google Scholar 

  214. Martel MA, Soriano FX, Baxter P, Rickman C, Duncan R, Wyllie DJA et al (2009) Inhibiting pro-death NMDA receptor signaling dependent on the NR2 PDZ ligand may not affect synaptic function or synaptic NMDA receptor signaling to gene expression. Channels 3(1):12–15

    Article  CAS  PubMed  Google Scholar 

  215. Lim IA, Merrill MA, Chen Y, Hell JW (2003) Disruption of the NMDA receptor-PSD-95 interaction in hippocampal neurons with no obvious physiological short-term effect. Neuropharmacology 45(6):738–754

    Article  CAS  PubMed  Google Scholar 

  216. Lim IA, Hall DD, Hell JW (2002) Selectivity and promiscuity of the first and second PDZ domains of PSD-95 and synapse-associated protein 102. J Biol Chem 277(24):21697–21711

    Article  CAS  PubMed  Google Scholar 

  217. Stiffler MA, Chen JR, Grantcharova VP, Lei Y, Fuchs D, Allen JE et al (2007) PDZ domain binding selectivity is optimized across the mouse proteome. Science 317(5836):364–369

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  218. Kim E, Sheng M (2004) PDZ domain proteins of synapses. Nat Rev Neurosci 5(10):771–781

    Article  CAS  PubMed  Google Scholar 

  219. Fan J, Cowan CM, Zhang LY, Hayden MR, Raymond LA (2009) Interaction of postsynaptic density protein-95 with NMDA receptors influences excitotoxicity in the yeast artificial chromosome mouse model of Huntington’s disease. J Neurosci 29(35):10928–10938

    Article  CAS  PubMed  Google Scholar 

  220. Bard L, Sainlos M, Bouchet D, Cousins S, Mikasova L, Breillat C et al (2010) Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins. Proc Natl Acad Sci U S A 107(45):19561–19566

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  221. Hardingham GE (2006) Pro-survival signalling from the NMDA receptor. Biochem Soc Trans 34(Pt 5):936–938

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  222. Kucharz K, Rasmussen IS, Bach A, Strømgaard K, Lauritzen M (2016) PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression. J Cereb Blood Flow Metab. doi:10.1177/0271678X16645595

    PubMed  Google Scholar 

  223. Chen Y, Brennan-Minnella AM, Sheth S, El-Benna J, Swanson RA (2015) Tat-NR2B9c prevents excitotoxic neuronal superoxide production. J Cereb Blood Flow Metab 35(5):739–742

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  224. Brennan-Minnella AM, Shen Y, Swanson RA (2013) Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death. Cell Death Dis 4, e580

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  225. Wang YB, Wang JJ, Wang SH, Liu SS, Cao JY, Li XM et al (2012) Adaptor protein APPL1 couples synaptic NMDA receptor with neuronal prosurvival phosphatidylinositol 3-kinase/Akt pathway. J Neurosci 32(35):11919–11929

    Article  CAS  PubMed  Google Scholar 

  226. Zhang L, Wu J, Duan X, Tian X, Shen H, Sun Q et al (2016) NADPH oxidase: a potential target for treatment of stroke. Oxid Med Cell Longev 2016:5026984

    PubMed Central  PubMed  Google Scholar 

  227. Radermacher KA, Wingler K, Kleikers P, Altenhofer S, Jr Hermans J, Kleinschnitz C et al (2012) The 1027th target candidate in stroke: will NADPH oxidase hold up? Exp Transl Stroke Med 4(1):11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  228. Walder CE, Green SP, Darbonne WC, Mathias J, Rae J, Dinauer MC et al (1997) Ischemic stroke injury is reduced in mice lacking a functional NADPH oxidase. Stroke 28(11):2252–2258

    Article  CAS  PubMed  Google Scholar 

  229. Kunz A, Anrather J, Zhou P, Orio M, Iadecola C (2007) Cyclooxygenase-2 does not contribute to postischemic production of reactive oxygen species. J Cereb Blood Flow Metab 27(3):545–551

    Article  CAS  PubMed  Google Scholar 

  230. Kahles T, Luedike P, Endres M, Galla HJ, Steinmetz H, Busse R et al (2007) NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 38(11):3000–3006

    Article  CAS  PubMed  Google Scholar 

  231. Chen H, Song YS, Chan PH (2009) Inhibition of NADPH oxidase is neuroprotective after ischemia-reperfusion. J Cereb Blood Flow Metab 29(7):1262–1272

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  232. Jackman KA, Miller AA, De Silva TM, Crack PJ, Drummond GR, Sobey CG (2009) Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice. Br J Pharmacol 156(4):680–688

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  233. Brait VH, Jackman KA, Walduck AK, Selemidis S, Diep H, Mast AE et al (2010) Mechanisms contributing to cerebral infarct size after stroke: gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J Cereb Blood Flow Metab 30(7):1306–1317

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  234. Chen H, Kim GS, Okami N, Narasimhan P, Chan PH (2011) NADPH oxidase is involved in post-ischemic brain inflammation. Neurobiol Dis 42(3):341–348

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  235. Tang XN, Zheng Z, Giffard RG, Yenari MA (2011) Significance of marrow-derived nicotinamide adenine dinucleotide phosphate oxidase in experimental ischemic stroke. Ann Neurol 70(4):606–615

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  236. De Silva TM, Brait VH, Drummond GR, Sobey CG, Miller AA (2011) Nox2 oxidase activity accounts for the oxidative stress and vasomotor dysfunction in mouse cerebral arteries following ischemic stroke. PLoS One 6(12), e28393

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  237. Radermacher KA, Wingler K, Langhauser F, Altenhofer S, Kleikers P, Hermans JJR et al (2013) Neuroprotection after stroke by targeting NOX4 as a source of oxidative stress. Antioxid Redox Signal 18(12):1418–1427

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  238. Suh SW, Shin BS, Ma H, Van Hoecke M, Brennan AM, Yenari MA et al (2008) Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol 64(6):654–663

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  239. Cifuentes-Pagano E, Meijles DN, Pagano PJ (2014) The quest for selective Nox inhibitors and therapeutics: challenges, triumphs and pitfalls. Antioxid Redox Signal 20(17):2741–2754

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  240. Wind S, Beuerlein K, Eucker T, Muller H, Scheurer P, Armitage ME et al (2010) Comparative pharmacology of chemically distinct NADPH oxidase inhibitors. Br J Pharmacol 161(4):885–898

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  241. Jaquet V, Scapozza L, Clark RA, Krause KH, Lambeth JD (2009) Small-molecule NOX Inhibitors: ROS-generating NADPH oxidases as therapeutic targets. Antioxid Redox Signal 11(10):2535–2552

    Article  CAS  PubMed  Google Scholar 

  242. Altenhofer S, Radermacher KA, Kleikers PWM, Wingler K, Schmidt HHHW (2015) Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxid Redox Signal 23(5):406–427

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  243. Aldieri E, Riganti C, Polimeni M, Gazzano E, Lussiana C, Campia I et al (2008) Classical inhibitors of NOX NAD(P)H oxidases are not specific. Curr Drug Metab 9(8):686–696

    Article  CAS  PubMed  Google Scholar 

  244. Wingler K, Altenhoefer SA, Kleikers PWM, Radermacher KA, Kleinschnitz C, Schmidt HHHW (2012) VAS2870 is a pan-NADPH oxidase inhibitor. Cell Mol Life Sci 69(18):3159–3160

    Article  CAS  PubMed  Google Scholar 

  245. Altenhofer S, Kleikers PW, Radermacher KA, Scheurer P, Rob Hermans JJ, Schiffers P et al (2012) The NOX toolbox: validating the role of NADPH oxidases in physiology and disease. Cell Mol Life Sci 69(14):2327–2343

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  246. Sun QA, Hess DT, Wang BL, Miyagi M, Stamler JS (2012) Off-target thiol alkylation by the NADPH oxidase inhibitor 3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine (VAS2870). Free Radic Biol Med 52(9):1897–1902

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  247. Schildknecht S, Weber A, Gerding HR, Pape R, Robotta M, Drescher M et al (2014) The NOX1/4 inhibitor GKT136901 as selective and direct scavenger of peroxynitrite. Curr Med Chem 21(3):365–376

    Article  CAS  PubMed  Google Scholar 

  248. Laleu B, Gaggini F, Orchard M, Fioraso-Cartier L, Cagnon L, Houngninou-Molango S et al (2010) First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis. J Med Chem 53(21):7715–7730

    Article  CAS  PubMed  Google Scholar 

  249. Rey FE, Cifuentes ME, Kiarash A, Quinn MT, Pagano PJ (2001) Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. Circ Res 89(5):408–414

    Article  CAS  PubMed  Google Scholar 

  250. Leto TL, Adams AG, de Mendez I (1994) Assembly of the phagocyte NADPH oxidase: binding of Src homology 3 domains to proline-rich targets. Proc Natl Acad Sci U S A 91(22):10650–10654

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  251. Finan P, Shimizu Y, Gout I, Hsuan J, Truong O, Butcher C et al (1994) An SH3 domain and proline-rich sequence mediate an interaction between two components of the phagocyte NADPH oxidase complex. J Biol Chem 269(19):13752–13755

    CAS  PubMed  Google Scholar 

  252. Raz L, Zhang QG, Zhou CF, Han D, Gulati P, Yang LC et al (2010) Role of Rac1 GTPase in NADPH oxidase activation and cognitive impairment following cerebral ischemia in the rat. PLoS One 5(9), e12606

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  253. Zhang QG, Raz L, Wang RM, Han D, De Sevilla L, Yang F et al (2009) Estrogen attenuates ischemic oxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation. J Neurosci 29(44):13823–13836

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  254. Selemidis S, Sobey CG, Wingler K, Schmidt HHHW, Drummond GR (2008) NADPH oxidases in the vasculature: Molecular features, roles in disease and pharmacological inhibition. Pharmacol Ther 120(3):254–291

    Article  CAS  PubMed  Google Scholar 

  255. Csanyi G, Cifuentes-Pagano E, Al Ghouleh I, Ranayhossaini DJ, Egana L, Lopes LR et al (2011) Nox2 B-loop peptide, Nox2ds, specifically inhibits the NADPH oxidase Nox2. Free Radic Biol Med 51(6):1116–1125

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  256. Cifuentes-Pagano E, Csanyi G, Pagano PJ (2012) NADPH oxidase inhibitors: a decade of discovery from Nox2ds to HTS. Cell Mol Life Sci 69(14):2315–2325

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  257. Bosco EE, Kumar S, Marchioni F, Biesiada J, Kordos M, Szczur K et al (2012) Rational design of small molecule inhibitors targeting the Rac GTPase-p67(phox) signaling axis in inflammation. Chem Biol 19(2):228–242

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  258. Smith SM, Min J, Ganesh T, Diebold B, Kawahara T, Zhu Y et al (2012) Ebselen and congeners inhibit NADPH oxidase 2-dependent superoxide generation by interrupting the binding of regulatory subunits. Chem Biol 19(6):752–763

    Google Scholar 

  259. Magesh S, Chen Y, Hu L (2012) Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev 32(4):687–726

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  260. Baird L, Lleres D, Swift S, Dinkova-Kostova AT (2013) Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci U S A 110(38):15259–15264

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  261. Johnson JA, Johnson DA, Kraft AD, Calkins MJ, Jakel RJ, Vargas MR et al (2008) The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann N Y Acad Sci 1147:61–69

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  262. Wells G (2015) Peptide and small molecule inhibitors of the Keap1-Nrf2 protein-protein interaction. Biochem Soc Trans 43:674–679

    Article  CAS  PubMed  Google Scholar 

  263. Surh YJ, Kundu JK, Na HK (2008) Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 74(13):1526–1539

    Article  CAS  PubMed  Google Scholar 

  264. Prosperini L, Pontecorvo S (2016) Dimethyl fumarate in the management of multiple sclerosis: appropriate patient selection and special considerations. Ther Clin Risk Manag 12:339–350

    Article  PubMed Central  PubMed  Google Scholar 

  265. Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P et al (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678–692

    Article  PubMed  Google Scholar 

  266. Hancock R, Bertrand HC, Tsujita T, Naz S, El-Bakry A, Laoruchupong J et al (2012) Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction. Free Radic Biol Med 52(2):444–451

    Article  CAS  PubMed  Google Scholar 

  267. Hancock R, Schaap M, Pfister H, Wells G (2013) Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction with improved binding and cellular activity. Org Biomol Chem 11(21):3553–3557

    Article  CAS  PubMed  Google Scholar 

  268. Hu L, Magesh S, Chen L, Wang L, Lewis TA, Chen Y et al (2013) Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorg Med Chem Lett 23(10):3039–3043

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  269. Jnoff E, Albrecht C, Barker JJ, Barker O, Beaumont E, Bromidge S et al (2014) Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex. ChemMedChem 9(4):699–705

    Article  CAS  PubMed  Google Scholar 

  270. Marcotte D, Zeng W, Hus JC, McKenzie A, Hession C, Jin P et al (2013) Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg Med Chem 21(14):4011–4019

    Article  CAS  PubMed  Google Scholar 

  271. Jiang ZY, Lu MC, Xu LL, Yang TT, Xi MY, Xu XL et al (2014) Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem 57(6):2736–2745

    Article  CAS  PubMed  Google Scholar 

  272. Jiang ZY, Xu LL, Lu MC, Chen ZY, Yuan ZW, Xu XL et al (2015) Structure-activity and structure-property relationship and exploratory in vivo evaluation of the nanomolar Keap1-Nrf2 protein-protein interaction inhibitor. J Med Chem 58(16):6410–6421

    Article  CAS  PubMed  Google Scholar 

  273. Jain AD, Potteti H, Richardson BG, Kingsley L, Luciano JP, Ryuzoji AF et al (2015) Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators. Eur J Med Chem 103:252–268

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  274. Winkel AF, Engel CK, Margerie D, Kannt A, Szillat H, Glombik H et al (2015) Characterization of RA839, a noncovalent small molecule binder to Keapl and selective activator of Nrf2 signaling. J Biol Chem 290(47):28446–28455

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  275. Bertrand HC, Schaap M, Baird L, Georgakopoulos ND, Fowkes A, Thiollier C et al (2015) Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction. J Med Chem 58(18):7186–7194

    Article  CAS  PubMed  Google Scholar 

  276. Davies TG, Wixted WE, Coyle JE, Griffiths-Jones C, Hearn K, McMenamin R et al (2016) Monoacidic inhibitors of the Kelch-like ECH-associated protein 1: nuclear factor erythroid 2-related factor 2 (KEAP1:NRF2) protein-protein interaction with high cell potency identified by fragment-based discovery. J Med Chem 59(8):3991–4006

    Article  CAS  PubMed  Google Scholar 

  277. Shimozono R, Asaoka Y, Yoshizawa Y, Aoki T, Noda H, Yamada M et al (2013) Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model. Mol Pharmacol 84(1):62–70

    Article  CAS  PubMed  Google Scholar 

  278. Sun HP, Jiang ZY, Zhang MY, Lu MC, Yang TT, Pan Y et al (2014) Novel protein-protein interaction inhibitor of Nrf2-Keap1 discovered by structure-based virtual screening. Med Chem Commun 5(1):93–98

    Article  CAS  Google Scholar 

  279. Zhuang C, Narayanapillai S, Zhang W, Sham YY, Xing C (2014) Rapid identification of Keap1-Nrf2 small-molecule inhibitors through structure-based virtual screening and hit-based substructure search. J Med Chem 57(3):1121–1126

    Article  CAS  PubMed  Google Scholar 

  280. Shah ZA, Li RC, Thimmulappa RK, Kensler TW, Yamamoto M, Biswal S et al (2007) Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury. Neuroscience 147(1):53–59

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  281. Shih AY, Li P, Murphy TH (2005) A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J Neurosci 25(44):10321–10335

    Article  CAS  PubMed  Google Scholar 

  282. Ding Y, Chen MC, Wang M, Wang MM, Zhang TJ, Park JS et al (2014) Neuroprotection by acetyl-11-keto-beta-boswellic acid, in ischemic brain injury involves the Nrf2/HO-1 defense pathway. Sci Rep 4:7002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  283. Lin-Holderer J, Li L, Gruneberg D, Marti HH, Kunze R (2016) Fumaric acid esters promote neuronal survival upon ischemic stress through activation of the Nrf2 but not the HIF-1 signaling pathway. Neuropharmacology 105:228–240

    Article  CAS  PubMed  Google Scholar 

  284. Wang JA, Fields J, Zhao CY, Langer J, Thimmulappa RK, Kensler TW et al (2007) Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic Biol Med 43(3):408–414

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  285. Zhao XR, Sun GH, Zhang J, Strong R, Dash PK, Kan YW et al (2007) Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke 38(12):3280–3286

    Article  CAS  PubMed  Google Scholar 

  286. Zhao XR, Sun GH, Zhang J, Ting SM, Gonzales N, Aronowski J (2015) Dimethyl fumarate protects brain from damage produced by intracerebral hemorrhage by mechanism involving Nrf2. Stroke 46(7):1923–1928

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  287. Zhao J, Redell JB, Moore AN, Dash PK (2011) A novel strategy to activate cytoprotective genes in the injured brain. Biochem Biophys Res Commun 407(3):501–506

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  288. Tu JY, Zhang X, Zhu Y, Dai YX, Li N, Yang F et al (2015) Cell-permeable peptide targeting the Nrf2-Keap1 interaction: a potential novel therapy for global cerebral ischemia. J Neurosci 35(44):14727–14739

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  289. Morphy R, Rankovic Z (2009) Designing multiple ligands—medicinal chemistry strategies and challenges. Curr Pharm Des 15(6):587–600

    Article  CAS  PubMed  Google Scholar 

  290. Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M et al (2008) Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 51(3):347–372

    Article  CAS  PubMed  Google Scholar 

  291. Cimino M, Gelosa P, Gianella A, Nobili E, Tremoli E, Sironi L (2007) Statins: multiple mechanisms of action in the ischemic brain. Neuroscientist 13(3):208–213

    Article  CAS  PubMed  Google Scholar 

  292. Lapchak PA (2013) Drug-like property profiling of novel neuroprotective compounds to treat acute ischemic stroke: guidelines to develop pleiotropic molecules. Transl Stroke Res 4(3):328–342

    Article  CAS  PubMed  Google Scholar 

  293. Congreve M, Chessari G, Tisi D, Woodhead AJ (2008) Recent developments in fragment-based drug discovery. J Med Chem 51(13):3661–3680

    Article  CAS  PubMed  Google Scholar 

  294. Hajduk PJ, Greer J (2007) A decade of fragment-based drug design: strategic advances and lessons learned. Nat Rev Drug Discov 6(3):211–219

    Article  CAS  PubMed  Google Scholar 

  295. Murray CW, Verdonk ML, Rees DC (2012) Experiences in fragment-based drug discovery. Trends Pharmacol Sci 33(5):224–232

    Article  CAS  PubMed  Google Scholar 

  296. Rees DC, Congreve M, Murray CW, Carr R (2004) Fragment-based lead discovery. Nat Rev Drug Discov 3(8):660–672

    Article  CAS  PubMed  Google Scholar 

  297. Bottegoni G, Favia AD, Recanatini M, Cavalli A (2012) The role of fragment-based and computational methods in polypharmacology. Drug Discov Today 17(1-2):23–34

    Article  CAS  PubMed  Google Scholar 

  298. Morphy R, Rankovic Z (2007) Fragments, network biology and designing multiple ligands. Drug Discov Today 12(3-4):156–160

    Article  CAS  PubMed  Google Scholar 

  299. Anighoro A, Bajorath J, Rastelli G (2014) Polypharmacology: challenges and opportunities in drug discovery. J Med Chem 57(19):7874–7887

    Article  CAS  PubMed  Google Scholar 

  300. Achenbach J, Klingler FM, Blocher R, Moser D, Hafner AK, Rodl CB et al (2013) Exploring the chemical space of multitarget ligands using aligned self-organizing maps. ACS Med Chem Lett 4(12):1169–1172

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  301. Prati F, De Simone A, Bisignano P, Armirotti A, Summa M, Pizzirani D et al (2015) Multitarget drug discovery for Alzheimer’s disease: triazinones as BACE-1 and GSK-3 beta inhibitors. Angew Chem Int Ed 54(5):1578–1582

    Article  CAS  Google Scholar 

  302. Shang EC, Yuan YX, Chen XY, Liu Y, Pei JF, Lai LH (2014) De novo design of multitarget ligands with an iterative fragment-growing strategy. J Chem Inf Model 54(4):1235–1241

    Article  CAS  PubMed  Google Scholar 

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Conflict of Interest

The author is the cofounder of Avilex Pharma, which develops peptide-based PSD-95 inhibitors for stroke treatment.

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  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, 2100, Denmark

    Anders Bach

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  1. Department of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Paul A. Lapchak

  2. Loma Linda University School of Medicine, Loma Linda, California, USA

    John H. Zhang

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Bach, A. (2017). Targeting Oxidative Stress in Stroke. In: Lapchak, P., Zhang, J. (eds) Neuroprotective Therapy for Stroke and Ischemic Disease. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-45345-3_8

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