Nitrones as therapeutics

Free Radical Biology and Medicine

Volumn 45, Issue 10, 2008, Pages 1361-1374

  Floyd, Robert A ^a,b   Kopke, Richard D ^a,c,d   Choi, Chul Hee ^a,c   Foster, Steven B ^a   Doblas, Sabrina ^a   Towner, Rheal A ^a  

^a OKLAHOMA MEDICAL RESEARCH FOUNDATION   (United States)

^b UNIVERSITY OF OKLAHOMA COLLEGE OF MEDICINE   (United States)

^c HOUGH EAR INSTITUTE   (United States)

^d UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER   (United States)

Author keywords

Acoustical trauma; Free radicals; Glioma; Hearing loss; Hepatocellular carcinoma; Nitrones; Stroke

Indexed keywords

2 HYDROXY N TERT BUTYL ALPHA PHENYLNITRONE; 2 SULFONYL N TERT BUTYL ALPHA PHENYLNITRONE; 3 HYDROXY N TERT BUTYL ALPHA PHENYLNITRONE; 4 HYDROXY N TERT BUTYL ALPHA PHENYLNITRONE; ACETYLCARNITINE; ACETYLCYSTEINE; ALPHA TOCOPHEROL; ANTIOXIDANT; BUTYLCRESOL; DISUFENTON SODIUM; EBSELEN; EDAVARONE; FREE RADICAL; N TERT BUTYL ALPHA PHENYLNITRONE; NITRONE DERIVATIVE; PLACEBO; TIRILAZAD; UNCLASSIFIED DRUG;

ACUTE KIDNEY FAILURE; AGING; ALZHEIMER DISEASE; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; BIRTH DEFECT; BRAIN ISCHEMIA; BRAIN PROTECTION; CEREBROVASCULAR ACCIDENT; CLINICAL TRIAL; CONGENITAL MALFORMATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG MECHANISM; DRUG STRUCTURE; GLIOMA; HEARING LOSS; HUMAN; LIVER CELL CARCINOMA; NEOPLASM; NOISE INJURY; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PRECANCER; PRIORITY JOURNAL; REVIEW; SEPTIC SHOCK; SPIN TRAPPING; STREPTOZOCIN DIABETES; STROKE; VISUAL DISORDER;

AGING; ANIMALS; ANTINEOPLASTIC AGENTS; ANTIOXIDANTS; HEARING LOSS; HUMANS; NEOPLASMS; NITROGEN OXIDES; STROKE;

ANIMALIA;

EID: 54349115127     PISSN: 08915849     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.freeradbiomed.2008.08.017     Document Type: Review

References (189)

1. Iwamura M., and Inamoto N. Novel formation of nitroxide radicals by radical addition to nitrones. Bull. Chem. Soc. Jpn. 40 (1967) 703
2. Janzen E.G., and Blackburn B.J. Detection and identification of short-lived free radicals by electron spin resonance trapping techniques (spin trapping): photolysis of organolead, -tin, and -mercury compounds. J. Am. Chem. Soc. 91 (1969) 4481-4490
3. Janzen E.G. Spin trapping. Acc. Chem. Res. 4 (1971) 31-40
4. Harbour J.R., and Bolton J.R. Superoxide formation in spinach chloroplasts: electron spin resonance detection by spin trapping. Biochem. Biophys. Res. Commun. 64 (1975) 803-807
5. 4-dependent microsomal lipid peroxidation. Fed. Proc. 35 (1976) 421
6. Barr D.P., Gunther M.R., Deterding L.J., Tomer K.B., and Mason R.P. ESR spin-trapping of a protein-derived tyrosyl radical from the reaction of cytochrome c with hydrogen peroxide. J. Biol. Chem. 271 (1996) 15498-15503
7. Chamulitrat W., and Mason R.P. Alkyl free radicals from the β scission of fatty acid alkoxyl radicals as detected by spin trapping in a lipoxygenase system. Arch. Biochem. Biophys. 282 (1990) 65-69
8. Fischer V., Harman L.S., West P.R., and Mason R.P. Direct electron spin resonance detection of free radical intermediates during the peroxidase catalyzed oxidation of phenacetin metabolites. Chem. Biol. Interact. 60 (1986) 115-127
9. Kalyanaraman B., Mottley C., and Mason R.P. A direct electron spin resonance and spin-trapping investigation of peroxyl free radical formation by hematin/hydroperoxide systems. J. Biol. Chem. 258 (1983) 3855-3858
10. Kalyanaraman B., Perez-Reyes E., and Mason R.P. Spin-trapping and direct electron spin resonance investigations of the redox metabolism of quinone anticancer drugs. Biochim. Biophys. Acta 630 (1980) 119-130
11. Saprin A.N., and Piette L.H. Spin trapping and its application in the study of lipid peroxidation and free radical production with liver microsomes. Arch. Biochem. Biophys. 180 (1977) 480-492
12. Yamazaki I., and Piette L.H. EPR spin-trapping study on the oxidizing species formed in the reaction of the ferrous ion with hydrogen peroxide. J. Am. Chem. Soc. 113 (1991) 7588-7593
13. 2 reactive species in oxygen toxicity in biology. J. Biol. Chem. 265 (1990) 13589-13594
14. Yamazaki I., Piette L.H., and Grover T.A. Kinetic studies on spin trapping of superoxide and hydroxyl radicals generated in NADPH-cytochrome P-450 reductase-paraquat systems: effect of iron chelates. J. Biol. Chem. 265 (1990) 652-659
15. Kalyanaraman B., Felix C.C., and Sealy R.C. Photoionization of melanin precursors: an electron spin resonance investigation using the spin trap 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). Photochem. Photobiol. 36 (1982) 5-12
16. Kalyanaraman B., Karoui H., Singh R.J., Tordo P., and Hogg N. Spin trapping of superoxide and carbon-centered radicals formed during autoxidation of tetrahydrobiopterin. Annu. Meet. Oxygen Soc. (1995) p.32 [Abstract]
17. Kalyanaraman B., Joseph J., and Parthasarathy S. The spin trap, αN-tert-butylnitrone, inhibits the oxidative modification of low density lipoprotein. FEBS Lett. 280 (1991) 17-20
18. Sheng P.G., Feix J., and Kalyanaraman B. Characterization of radical adducts formed during photochemical spin trapping in liposomes. Photochem. Photobiol. 52 (1990) 323-331
19. Floyd R.A., and Wiseman B.B. Spin-trapping free radicals in the autooxidation of 6-hydroxydopamine. Biochim. Biophys. Acta 586 (1979) 196-207
20. Floyd R.A., and Soong L.M. Spin trapping in biological systems: oxidation of the spin trap 5,5-dimethyl-1-pyrroline-1-oxide by a hydroperoxide-hematin system. Biochem. Biophys. Res. Commun. 74 (1977) 79-84
21. Floyd R.A., Soong L.M., Stuart M.A., and Reigh D.L. Spin trapping of free radicals produced from nitrosoamine carcinogens. Photochem. Photobiol. 28 (1978) 857-862
22. Poyer J.L., Floyd R.A., McCay P.B., Janzen E.G., and Davis E.R. Spin trapping of the trichloromethyl radical produced during enzymic NADPH oxidation in the presence of carbon tetrachloride or carbon bromotrichloromethane. Biochim. Biophys. Acta 539 (1978) 402-409
23. Wong P.K., Poyer J.L., DuBose C.M., and Floyd R.A. Hydralazine-dependent carbon dioxide free radical formation by metabolizing mitochondria. J. Biol. Chem. 263 (1988) 11296-11301
24. Zs.-Nagy I., and Floyd R.A. Hydroxyl free radical reactions with amino acids and proteins studies by electron spin resonance spectroscopy and spin trapping. Biochim. Biophys. Acta 790 (1984) 238-250
25. 4. Biochem. Pharmacol. 28 (1979) 2231-2235
26. 4-induced lipid peroxidation in mouse liver. Biochem. Pharmacol. 31 (1982) 405-409
27. McCay P.B., and Reinke L.A. Detection of reactive free radicals in livers of ethanol-fed rats: potentiating effect of high fat diets. In: Paoletti O., Kritchersky O., and Holmes W.L. (Eds). Drugs Affecting Lipid Metab (1987) 181-192
28. Lai E.K., Crossley C., Sridhar R., Misra H.P., Janzen E.G., and McCay P.B. In vivo spin trapping of free radicals generated in brain, spleen, and liver during γ-radiation of mice. Arch. Biochem. Biophys. 244 (1986) 156-160
29. Bolli R., Patel B.S., Jeroudi M.O., Lai E.K., and McCay P.B. Demonstration of free radical generation on "stunned" myocardium of intact dogs with the use of the spin trap αN-tert-butyl nitrone. J. Clin. Invest. 82 (1988) 476-485
30. Bolli R., Jeroudi M.O., Patel B.S., DuBose C.M., Lai E.K., Roberts R., and McCay P.B. Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. Proc. Natl. Acad. Sci. USA 86 (1989) 4695-4699
31. Bolli R., Patel B.S., Jeroudi M.O., Li X.Y., Triana J.F., Lai E.K., and McCay P.B. Iron-mediated radical reactions upon reperfusion contribute to myocardial "stunning". Am. J. Physiol. 259 (1990) H1901-H1911
32. Bolli R., Jeroudi M.O., Patel B.S., Aruoma O.I., Halliwell B., Lai E.K., and McCay P.B. Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Circ. Res. 65 (1989) 607-622
33. Bolli R., and McCay P.B. Use of spin traps in intact animals undergoing myocardial ischemia/reperfusion: a new approach to assessing the role of oxygen radicals in myocardial "stunning.". Free Radic. Biol. Med. 9 (1990) 3-6
34. Chen G., Bray T.M., Janzen E.G., and McCay P.B. Excretion, metabolism and tissue distribution of a spin trapping agent, α-phenyl-N-tert-butyl-nitrone (PBN) in rats. Free Radic. Res. Commun. 9 (1990) 317-323
35. Chen G., Janzen E.G., Bray T.M., and McCay P.B. PBN and its applications in biology. In: Davies K.J.A., and Ursini F. (Eds). The Oxygen Paradox (1995), Cleup Univ. Press, Padova 790-800
36. Floyd R.A. Protective action of nitrone-based free radical traps against oxidative damage to the central nervous system. Adv. Pharmacol. 38 (1997) 361-378
37. Kotake Y. Pharmacologic properties of phenyl N-tert-butylnitrone. Antioxid. Redox Signaling 1 (1999) 481-499
38. Floyd R.A., Hensley K., Forster M.J., Kelleher-Anderson J.A., and Wood P.L. Nitrones as neuroprotectants and antiaging drugs. Ann. N. Y. Acad. Sci. 959 (2002) 321-329
39. Maples K.R., Green A.R., and Floyd R.A. Nitrone-related therapeutics: potential of NXY-059 for the treatment of acute ischaemic stroke. CNS Drugs 18 (2004) 1071-1084
40. Novelli G., Angiolini P., Cansales G., Lippi R., and Tani R. Anti-shock action of phenyl-t-butyl-nitrone, a spin trapper. In: Novelli G.P., and Ursini F. (Eds). Oxygen Free Radicals in Shock (1986), Karger, Basel 119-124
41. Novelli G.P., Angiolini P., Tani R., Consales G., and Bordi L. Phenyl-t-butyl-nitrone is active against traumatic shock in rats. Free Radic. Res. Commun. 1 (1985) 321-327
42. Novelli G.P., Anglolini P., and Tani R. The spin trap phenyl butyl nitrone prevents lethal shock in the rat. In: Poll G., Cheeseman K.H., Dianzani M.U., and Slater T.F. (Eds). Free Radicals in Liver Injury (1986), IRL Press, Oxford 225-228
43. McKechnie K., Furman B.L., and Parratt J.R. Modification by oxygen free radical scavengers of the metabolic and cardiovascular effects of endotoxin infusion in conscious rats. Circ. Shock 19 (1986) 429-439
44. Hamburger S.A., and McCay P.B. Endotoxin-induced mortality in rats is reduced by nitrones. Circ. Shock 29 (1989) 329-334
45. Pogrebniak H.W., Merino M.J., Hahn S.M., Mitchell J.B., and Pass H.I. Spin trap salvage from endotoxemia: the role of cytokine down-regulation. Surgery 112 (1992) 130-139
46. Floyd R.A. Role of oxygen free radicals in carcinogenesis and brain ischemia. FASEB J. 4 (1990) 2587-2597
47. Carney J.M., Starke-Reed P.E., Oliver C.N., Landrum R.W., Chen M.S., Wu J.F., and Floyd R.A. Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-α-phenylnitrone. Proc. Natl. Acad. Sci. USA 88 (1991) 3633-3636
48. Carney, J. M.; Floyd, R. A. Phenyl butyl nitrone compositions and methods for treatment of oxidative tissue damage. U.S. Patent 5025032; issued 18 June 1991.
49. Cao W., Carney J.M., Duchon A., Floyd R.A., and Chevion M. Oxygen free radical involvement in ischemia and reperfusion injury to brain. Neurosci. Lett. 88 (1988) 233-238
50. Phillis J.W., and Clough-Helfman C. Protection from cerebral ischemic injury in gerbils with the spin trap agent N-tertα-phenylnitrone (PBN). Neurosci. Lett. 116 (1990) 315-319
51. Cao X., and Phillis J.W. α-Phenyl-tert-butyl-nitrone reduces cortical infarct and edema in rats subjected to focal ischemia. Brain Res. 644 (1994) 267-272
52. Mori H., Arai T., Ishii H., Adachi T., Endo N., Makino K., and Mori K. Neuroprotective effects of pterin-6-aldehyde in gerbil global brain ischemia: comparison with those of α-phenyl-N-tert-butyl nitrone. Neurosci. Lett. 241 (1998) 99-102
53. Schulz J.B., Henshaw D.R., Siwek D., Jenkins B.G., Ferrante R.J., Cipolloni P.B., Kowall N.W., Rosen B.R., and Beal M.F. Involvement of free radicals in excitotoxicity in vivo. J. Neurochem. 64 (1995) 2239-2247
54. He Q.P., Smith M.L., Li P.A., and Siesjo B.K. Necrosis of the substantia nigra, pars reticulate in flurothys-induced status epilepticus is ameliorated by the spin trap α-N-butyl nitrone. Free Radic. Biol. Med. 22 (1997) 917-922
55. Floyd R.A., Hensley K., and Bing G. Evidence for enhanced neuro-inflammatory processes in neurodegenerative diseases and the action of nitrones as potential therapeutics. J. Neural Trans. 60 (2000) 337-364
56. Leib S.L., Kim Y.S., Chow L.L., Sheldon R.A., and Tauber M.G. Reactive oxygen intermediates contribute to necrotic and apoptotic neuronal injury in an infant rat model of bacterial meningitis due to group B streptococci. J. Clin. Invest. 98 (1996) 2632-2639
57. Marklund N., and Hillered L. The role of reactive oxygen species in traumatic brain injury: experimental studies in the rat (2001), Uppsala University, Uppsala [Ph.D. thesis]
58. Pitari G., Zingman L., Hodgson D., Alekseev A., Kazerounian S., Bienengraeber M., Hajniczky G., Terzic A., and Waldman S. Bacterial enterotoxins are associated with resistance to colon cancer. Proc. Natl. Acad. Sci. USA 100 (2003) 2695-2699
59. Marklund N., Lewander T., Clausen F., and Hillered L. Effects of the nitrone radical scavengers PBN and S-PBN on in vivo trapping of reactive oxygen species after traumatic brain injury in rats. J. Cereb. Blood Flow Metab. 21 (2001) 1259-1267
60. Marklund N., Sihver S., Langstrom B., Bergstrom M., and Hillered L. Effect of traumatic brain injury and nitrone radical scavengers on relative changes in regional cerebral blood flow and glucose uptake in rats. J. Neurotrauma 19 (2002) 1139-1153
61. Marklund N., Clausen F., Lewen A., Hovda D.A., Olsson Y., and Hillered L. α-Phenyl-tert-N-butyl nitrone (PBN) improves functional and morphological outcome after cortical contusion injury in the rat. Acta Neurochir. (Wien) 143 (2001) 73-81
62. Lewen A., Skoglosa Y., Clausen F., Marklund N., Chan P.H., Lindholm D., and Hillered L. Paradoxical increase in neuronal DNA fragmentation after neuroprotective free radical scavenger treatment in experimental traumatic brain injury. J. Cereb. Blood Flow Metab. 21 (2001) 344-350
63. Fechter L.D., Liu Y., and Pearce T.A. Cochlear protection from carbon monoxide exposure by free radical blockers in the guinea pig. Toxicol. Appl. Pharmacol. 142 (1997) 47-55
64. Tabatabaie T., Kotake Y., Wallis G., Jacob J.M., and Floyd R.A. Spin trapping agent phenyl N-tert-butylnitrone protects against the onset of drug-induced insulin-dependent diabetes mellitus. FEBS Lett. 407 (1997) 148-152
65. Parman T., Wiley M.J., and Wells P.G. Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat. Med. 5 (1999) 582-585
66. Pedraza-Chaverri J., Tapia E., and Bobadilla N. Ischemia-reperfusion induced acute renal failure in the rat is ameliorated by the spin-trapping agent α-pheny-N-tert-butyl nitrone (PBN). Renal Failure 14 (1992) 467-471
67. Ranchon I., LaVail M.M., Kotake Y., and Anderson R.E. Free radical trap phenyl-N-tert-butylnitrone protects against light damage but does not rescue P23H and S334ter rhodopsin transgenic rats from inherited retinal degeneration. J. Neurosci. 23 (2003) 6050-6057
68. Ranchon I., Chen S., Alvarez K., and Anderson R.E. Systemic administration of phenyl-N-tert-butylnitrone protects the retina from light damage. Invest. Ophthalmol. Visual Sci. 42 (2001) 1375-1379
69. Tomita H., Kotake Y., and Anderson R.E. Mechanism of protection from light-induced retinal degeneration by the synthetic antioxidant phenyl-N-tert-butylnitrone. Invest. Ophthalmol. Visual Sci. 46 (2005) 427-434
70. Saito K., Yoshioka H., and Cutler R.G. A spin trap, N-tert-butyl-α-phenylnitrone extends the life span of mice. Biosci. Biotechnol. Biochem. 62 (1998) 792-794
71. Edamatsu R., Mori A., and Packer L. The spin-trap N-tert-α-phenyl-butylnitrone prolongs the life span of the senescence accelerated mouse. Biochem. Biophys. Res. Commun. 211 (1995) 847-849
72. Sack C.A., Socci D.J., Crandall B.M., and Arendash G.W. Antioxidant treatment with phenyl-α-tert-butyl nitrone (PBN) improves the cognitive performance and survival of aging rats. Neurosci. Lett. 205 (1996) 181-184
73. Floyd R.A. Oxidative damage to behavior during aging. Science 254 (1991) 1597
74. Miller R.A., Harrison D.E., Astle C.M., Floyd R.A., Flurkey K., Hensley K.L., Javors M.A., Leeuwenburgh C., Nelson J.F., Ongini E., Nadon N.L., Warner H.R., and Strong R. An aging interventions testing program: study design and interim report. Aging Cell 6 (2007) 565-575
75. Strong, R.; Miller, R. A.; Astle, C. M.; Floyd, R. A.; Flurkey, K.; Hensley, K. L.; Javors, M. A.; Leeuwenburgh, C.; Nelson, J. F.; Ongini, E.; Nadon, N. L.; Warner, H. R.; Harrison, D. E. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7:641-650; 2008.
76. Fan L.W., Tien L.T., Mitchell H.J., Rhodes P.G., and Cai Z. α-phenyl-N-tert-butyl-nitrone ameliorates hippocampal injury and improves learning and memory in juvenile rats following neonatal exposure to lipopolysaccharide. Eur. J. Neurosci. 27 (2008) 1475-1484
77. Zhao L., Chen Y.H., Wang H., Ji Y.L., Ning H., Wang S.F., Zhang C., Lu J.W., Duan Z.H., and Xu D.X. Reactive oxygen species contribute to lipopolysaccharide-induced teratogenesis in mice. Toxicol. Sci. 103 (2008) 149-157
78. Hobbs C.E., and Oorschot D.E. Neonatal rat hypoxia-ischemia: long-term rescue of striatal neurons and motor skills by combined antioxidant-hypothermia treatment. Brain Pathol. 18 (2008) 443-454
79. Floyd R.A., Hensley K., Forster M.J., Kelleher-Anderson J.A., and Wood P.L. Nitrones, their value as therapeutics and probes to understand aging. Mech. Ageing Dev. 123 (2001) 1021-1031
80. Floyd R.A. Nitrones as therapeutics in age-related diseases. Aging Cell 5 (2006) 51-57
81. Maples K.R., Jordan S.J., and Mason R.P. In vivo rat hemoglobin thiyl free radical formation following administration of phenylhydrazine and hydrazine-based drugs. Drug Metab. Dispos. 16 (1988) 799-803
82. Detweiler G.D., Deterding L.J., Tomer K.B., Chignell C.F., Germolec D., and Mason R.P. Immunological identification of the heart myoglobin radical formed by hydrogen peroxide. Free Radic. Biol. Med. 33 (2002) 364-369
83. Deterding L.J., Ramirez D.C., Dubin J.R., Mason R.P., and Tomer K.B. Identification of free radicals on hemoglobin from its self-peroxidation using mass spectrometry and immuno-spin trapping: observation of a histidinyl radical. J. Biol. Chem. 279 (2004) 11600-11607
84. Detweiler C.D., Lardinois O.M., Deterding L.J., de Montellano P.R., Tomer K.B., and Mason R.P. Identification of the myoglobin tyrosyl radical by immuno-spin trapping and its dimerization. Free Radic. Biol. Med. 38 (2005) 969-976
85. Bhattacharjee S., Deterding L.J., Jiang J., Bonini M.G., Tomer K.B., Ramirez D.C., and Mason R.P. Electron transfer between a tyrosyl radical and a cysteine residue in hemoproteins: spin trapping analysis. J. Am. Chem. Soc. 129 (2007) 13493-13501
86. Lardinois O.M., Detweiler C.D., Tomer K.B., Mason R.P., and Deterding L.J. Identifying the site of spin trapping in proteins by a combination of liquid chromatography, ELISA, and off-line tandem mass spectrometry. Free Radic. Biol. Med. 44 (2008) 893-906
87. Ramirez D.C., Mejiba S.E., and Mason R.P. Immuno-spin trapping of DNA radicals. Nat. Methods 3 (2006) 123-127
88. Bonini M.G., Siraki A.G., Atanassov B.S., and Mason R.P. Immunolocalization of hypochlorite-induced, catalase-bound free radical formation in mouse hepatocytes. Free Radic. Biol. Med. 42 (2007) 530-540
89. Ehrenshaft M., and Mason R.P. Protein radical formation on thyroid peroxidase during turnover as detected by immuno-spin trapping. Free Radic. Biol. Med. 41 (2006) 422-430
90. Janzen E.G., West M.S., and Poyer J.L. Comparison of antioxidant activity of PBN with hindered phenols in initiated rat liver microsomal lipid peroxidation. In: Asada K., and Toshikawa T. (Eds). Frontiers of Reactive Oxygen Species in Biology and Medicine (1994), Elsevier, San Diego 431-446
91. Barclay L.R.C., and Vinqvist M.R. Do spin traps also act as classical chain-breaking antioxidants? A quantitative kinetic study of phenyl-tert-butylnitrone (PBN) in solution and in liposomes. Free Radic. Biol. Med. 28 (2000) 1079-1090
92. Anderson D.E., Yuan X.J., Tseng C.M., Rubin L.J., Rosen G.M., and Tod M.L. Nitrone spin-traps block calcium channels and induce pulmonary artery relaxation independent of free radicals. Biochem. Biophys. Res. Commun. 193 (1993) 878-885
93. Milatovic D., Radic Z., Zivin M., and Dettbarn W.D. Atypical effect of some spin trapping agents: reversible inhibition of acetylcholinesterase. Free Radic. Biol. Med. 28 (2000) 597-603
94. Zivin M., Milatovic D., and Dettbarn W.D. Nitrone spin trapping compound N-tert-α-phenylnitrone prevents seizures induced by anticholinesterases. Brain Res. 850 (1999) 63-72
95. Milatovic D., Zivin M., Hustedt E., and Dettbarn W.D. Spin trapping agent phenyl-N-tert-butylnitrone prevents diisopropylphosphorofluoridate-induced excitotoxicity in skeletal muscle of the rat. Neurosci. Lett. 278 (2000) 25-28
96. Biegon A., Alvarado M., Budinger T.F., Grossman R., Hensley K., West M.S., Kotake Y., Ono M., and Floyd R.A. Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain. J. Neurochem. 82 (2002) 924-934
97. Kotake Y., Sang H., Miyajima T., and Wallis G.L. Inhibition of NF-κBκ, iNOS mRNA, COX2 mRNA, and COX catalytic activity by phenyl-N-tert-butylnitrone (PBN). Biochim. Biophys. Acta 1448 (1998) 77-84
98. Miyajima T., and Kotake Y. Spin trapping agent, phenyl N-tert-butyl nitrone, inhibits induction of nitric oxide synthase in endotoxin-induced shock in mice. Biochem. Biophys. Res. Commun. 215 (1995) 114-121
99. Endoh H., Kato N., Fujii S., Suzuki Y., Sato S., Kayama T., Kotake Y., and Yoshimura T. Spin trapping agent, phenyl N-tert-butylnitrone, reduces nitric oxide production in the rat brain during experimental meningitis. Free Radic. Res. 35 (2001) 583-591
100. Sang H., Wallis G.L., Stewart C.A., and Kotake Y. Expression of cytokines and activation of transcription factors in lipopolysaccharide-administered rats and their inhibition by phenyl N-tert-butylnitrone (PBN). Arch. Biochem. Biophys. 363 (1999) 341-348
101. Cuevas P., Garcia-Calvo M., Carceller F., Reimers D., Zazo M., Cuevas B., Munoz-Willery I., Martinez-Coso V., Lamas S., and Gimenez-Gallego G. Correction of hypertension by normalization of endothelial levels of fibroblast growth factor and nitric oxide synthase in spontaneously hypertensive rats. Proc. Natl. Acad. Sci. USA 93 (1996) 11996-12001
102. Tabatabaie T., Graham K.L., Vasquez A.M., Floyd R.A., and Kotake Y. Inhibition of the cytokine-mediated inducible nitric oxide synthase expression in rat insulinoma cells by phenyl N-tert-butylnitrone. Nitric Oxide 4 (2000) 157-167
103. Stewart C.A., Hyam K., Wallis G., Sang H., Robinson K.A., Floyd R.A., Kotake Y., and Hensley K. Phenyl-N-tert-butylnitrone demonstrates broad-spectrum inhibition of apoptosis-associated gene expression in endotoxin-treated rats. Arch. Biochem. Biophys. 365 (1999) 71-74
104. Kotake Y., Kishida H., Nakae D., and Floyd R.A. Nitric oxide production by primary liver cells isolated from amino acid diet fed rats. Methods Enzymol. 396 (2005) 535-541
105. Floyd R.A., Kotake Y., Towner R.A., Guo W.X., Nakae D., and Konishi Y. Nitric oxide and cancer development. J. Toxicol. Pathol. 20 (2007) 77-92
106. Green A.R., Ashwood T., Odergren T., and Jackson D.M. Nitrones as neuroprotective agents in cerebral ischemia, with particular reference to NXY-059. Pharmacol. Ther. 100 (2003) 195-214
107. Maples K.R., Ma F., and Zhang Y.K. Comparison of the radical trapping ability of PBN, S-PBN and NXY-059. Free Radic. Biol. Med. 34 (2001) 417-426
108. Marshall J.W., Green A.R., and Ridley R.M. Comparison of the neuroprotective effect of clomethiazole, AR-R15896AR and NXY-059 in a primate model of stroke using histological and behavioural measures. Brain Res. 972 (2003) 119-126
109. Marshall J.W., Cummings R.M., Bowes L.J., Ridley R.M., and Green A.R. 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 (2003) 2228-2233
110. Dehouck M.P., Cecchelli R., Green A.R., Renftel M., and Lundquist S. In vitro blood-brain barrier permeability and cerebral endothelial cell uptake of the neuroprotective nitrone compound NXY-059 in normoxic, hypoxic and ischemic conditions. Brain Res. 995 (2002) 229-235
111. Edenius C., Strid S., Borga O., Breitholtz-Emanuelsson A., Vallen K.L., and Fransson B. Pharmacokinetics of NXY-059, a nitrone-based free radical trapping agent, in healthy young and elderly subjects. J. Stroke Cerebrovasc. Dis. 11 (2002) 34-42
112. Nilsson D., Wemer J., Cheng Y.F., Reinholdsson I., Englund G., Egberg N., and Schulman S. NXY-059 does not affect bleeding time in healthy volunteers: a randomized, double-blind, placebo-controlled, 3-period crossover Phase I study. J. Clin. Pharmacol. 47 (2007) 264-272
113. Mutch N.J., Moore N.R., Mattsson C., Jonasson H., Green A.R., and Booth N.A. The use of the Chandler loop to examine the interaction potential of NXY-059 on the thrombolytic properties of rtPA on human thrombi in vitro. Br. J. Pharmacol. 153 (2008) 124-131
114. Cheng Y.F., Strid S., Borga O., Nilsson D., and Wemer J. Active renal secretion of NXY-059, a novel neuroprotectant, is mediated via an organic acid transporter. J. Clin. Pharmacol. 47 (2007) 909-914
115. Lees K.R., Zivin J.A., Ashwood T., Davalos A., Davis S.M., Diener H.C., Grotta J., Lyden P., Shuaib A., Hardemark H.G., and Wasiewski W.W. NXY-059 for acute ischemic stroke. N. Engl. J. Med. 354 (2006) 588-600
116. Saver J.L. 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 (2007) 1515-1518
117. Koziol J.A., and Feng A.C. 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 (2006) 2644-2647
118. Lees K.R., Davalos A., Davis S.M., Diener H.C., Grotta J., Lyden P., Shuaib A., Ashwood T., Hardemark H.G., Wasiewski W., Emeribe U., and Zivin J.A. Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial. Stroke 37 (2006) 2970-2978
119. Shuaib A., Lees K.R., Lyden P., Grotta J., Davalos A., Davis S.M., Diener H.C., Ashwood T., Wasiewski W.W., and Emeribe U. NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med. 357 (2007) 562-571
120. Diener H.C., Lees K.R., Lyden P., Grotta J., Davalos A., Davis S.M., Shuaib A., Ashwood T., Wasiewski W., Alderfer V., Hardemark H.G., and Rodichok L. NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II trials. Stroke 39 (2008) 1751-1758
121. Green A.R. Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly. Br. J. Pharmacol. 153 Suppl. 1 (2008) S325-S338
122. Ford G.A. Clinical pharmacological issues in the development of acute stroke therapies. Br. J. Pharmacol. 153 Suppl. 1 (2008) S112-S119
123. Feuerstein G.Z., Zaleska M.M., Krams M., Wang X., Day M., Rutkowski J.L., Finklestein S.P., Pangalos M.N., Poole M., Stiles G.L., Ruffolo R.R., and Walsh F.L. Missing steps in the STAIR case: a translational medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke. J. Cereb. Blood Flow Metab. 28 (2008) 217-219
124. Savitz S.I., and Fisher M. Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials. Ann. Neurol. 61 (2007) 396-402
125. Savitz S.I. 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 (2007) 20-25
126. Savitz S.I., and Schabitz W.R. A critique of SAINT II: wishful thinking, dashed hopes, and the future of neuroprotection for acute stroke. Stroke 39 (2008) 1389-1391
127. Wang C.X., and Shuaib A. Neuroprotective effects of free radical scavengers in stroke. Drugs Aging 24 (2007) 537-546
128. Hsiao K., Chapman P., Nilsen S., Eckman C., Haigaya Y., Younkin S., Yang F., and Cole G. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274 (1996) 99-102
129. Nakae D., Kishida H., Enami T., Konishi Y., Hensley K.L., Floyd R.A., and Kotake Y. Effects of phenyl N-tert-butyl nitrone and its derivatives on the early phase of hepatocarcinogenesis in rats fed a choline-deficient, L-amino acid-defined diet. Cancer Sci. 94 (2003) 26-31
130. Rattazzi M., Puato M., Faggin E., Bertipaglia B., Zambon A., and Pauletto P. C-reactive protein and interleukin-6 in vascular disease: culprits or passive bystanders?. J. Hypertens. 21 (2003) 1787-1803
131. Ghoshal A.K., and Farber E. The induction of liver cancer by dietary deficiency of choline and methionine without added carcinogens. Carcinogenesis 5 (1984) 1367-1370
132. Rushmore T.H., Ghazarian D.M., Subrahmanyan V., Farber E., and Ghoshal A.K. Probable free radical effects on rat liver nuclei during early hepatocarcinogenesis with a choline-devoid low methionine diet. Cancer Res. 47 (1987) 6731-6740
133. Ghoshal A.K., Rushmore T.H., Lim Y.P., and Farber E. Early detection of lipid peroxidation in the hepatic nuclei of rats fed a diet deficient in choline and methionine (CMD). Proc. Am. Assoc. Cancer Res. 25 (1984) 94
134. Ghoshal A.K., Laconi E., Willemsen F., Ghoshal A., Rushmore T.H., and Farber E. Modulation by calcium of the carcinogenic process in the liver induced by a choline-deficient diet. Can. J. Physiol. Pharmacol. 65 (1987) 478-482
135. 5 of pro-oxidant effects of choline deficiency. Free Radic. Biol. Med. 8 (1990) 3-7
136. Nakae D., Kotake Y., Kishida H., Hensley K.L., Denda A., Kobayashi Y., Kitayama W., Tsujiuchi T., Sang H., Stewart C.A., Tabatabaie T., Floyd R.A., and Konishi Y. Inhibition by phenyl N-tert-butyl nitrone on early phase carcinogenesis in the livers of rats fed a choline-deficient, l-amino acid-defined diet. Cancer Res. 58 (1998) 4548-4551
137. Floyd, R. A.; Kotake, Y.; Hensley, K.; Nakae, D. Nitrone inhibition of cancer development. U.S. Patent 6569902; issued 27 May 2003.
138. Floyd R.A., Kotake Y., Hensley K., Nakae D., and Konishi Y. Reactive oxygen species in choline deficiency induced carcinogenesis and nitrone inhibition. Mol. Cell. Biochem. 234/235 (2002) 195-203
139. Rincavage H.L., McDonnell D.P., and Kuhn C.M. Expression of functional estrogen receptor β in locus coeruleus-derived cath.a cells. Endocrinology 144 (2003) 2829-2835
140. Torok N.J., Higuchi H., Bronk S., and Gores G.J. Nitric oxide inhibits apoptosis downstream of cytochrome c release by nitrosylating caspase 9. Cancer Res. 62 (2002) 1648-1653
141. Radisavljevic Z. Nitric oxide suppression triggers apoptosis through the FKHRL1 (FOXO3A)/ROCK kinase pathway in human breast carcinoma cells. Cancer 97 (2003) 1358-1363
142. Salvucci O., Carsana M., Bersani I., Tragni G., and Anichini A. Antiapoptotic role of endogenous nitric oxide in human melanoma cells. Cancer Res. 61 (2001) 318-326
143. Kim Y.M., deVera M.E., Watkins S.C., and Billiar T.R. Nitric oxide protects cultured rat hepatocytes from tumor necrosis factor-α-induced apoptosis by inducing heat shock protein 70 expression. J. Biol. Chem. 272 (1997) 1402-1411
144. Kim Y.M., Talanian R.V., and Billiar T.R. Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms. J. Biol. Chem. 272 (1997) 31138-31148
145. Tzeng E., Billiar T.R., Williams D.L., Li J., Lizonova A., Kovesdi I., and Kim Y.M. Adenovirus-mediated inducible nitric oxide synthase gene transfer inhibits hepatocyte apoptosis. Surgery 124 (1998) 278-283
146. Li J., Bombeck C.A., Yang S., Kim Y.M., and Billiar T.R. Nitric oxide suppresses apoptosis via interrupting caspase activation and mitochondrial dysfunction in cultured hepatocytes. J. Biol. Chem. 274 (1999) 17325-17333
147. Kim Y.M., Kim T.H., Chung H.T., Talanian R.V., Yin X.M., and Billiar T.R. Nitric oxide prevents tumor necrosis factor alpha-induced rat hepatocyte apoptosis by the interruption of mitochondrial apoptotic signaling through S-nitrosylation of caspase-8. Hepatology 32 (2000) 770-778
148. Kim Y.M., Chung H.T., Simmons R.L., and Billiar T.R. Cellular non-heme iron content is a determinant of nitric oxide-mediated apoptosis, necrosis, and caspase inhibition. J. Biol. Chem. 275 (2000) 10954-10961
149. Stolz D.B., Zamora R., Vodovotz Y., Loughran P.A., Billiar T.R., Kim Y.M., Simmons R.L., and Watkins S.C. Peroxisomal localization of inducible nitric oxide synthase in hepatocytes. Hepatology 36 (2002) 81-93
150. Azad N., Vallyathan V., Wang L., Tantishaiyakul V., Stehlik C., Leonard S.S., and Rojanasakul Y. S-nitrosylation of Bcl-2 inhibits its ubiquitin-proteasomal degradation: a novel antiapoptotic mechanism that suppresses apoptosis. J. Biol. Chem. 281 (2006) 34124-34134
151. Jaiswal M., LaRusso N.F., Nishioka N., Nakabeppu Y., and Gores G.J. Human Ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide. Cancer Res. 61 (2001) 6388-6393
152. Delgado-Esteban M., Martin-Zanca D., Andres-Martin L., Almeida A., and Bolaños J.P. Inhibition of PTEN by peroxynitrite activates the phosphoinositide-3-kinase/Akt neuroprotective signaling pathway. J. Neurochem. 102 (2007) 194-205
153. Yu C.X., Li S., and Whorton A.R. Redox regulation of PTEN by S-nitrosothiols. Mol. Pharmacol. 68 (2005) 847-854
154. Doblas S., Saunders D., Tesiram Y., Kshirsager P., Pye Q., Oblander J., Gordon B., Kosanke S., Floyd R.A., and Towner R.A. Phenyl-tert-butyl-nitrone induces tumor regression and decreases angiogenesis in a C6 rat glioma model. Free Radic. Biol. Med. 44 (2007) 63-72
155. Vergely C., Renard C., Moreau D., Sarrado C., Roubaud V., Tuccio B., and Rochette L. Effect of two new PBN-derived phosphorylated nitrones against postischaemic ventricular dysrhythmias. Fundam. Clin. Pharmacol. 17 (2003) 433-442
156. Cobbs C.S., Brenman J.E., Aldape K.D., Bredt D.S., and Israel M.A. Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res. 55 (1995) 727-730
157. Lala P.K., and Chakraborty C. Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol. 2 (2001) 149-156
158. Xie Q., Whisnant R., and Nathan C. Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J. Exp. Med. 177 (1993) 1779-1784
159. Asanuma, T.; Tesiram, Y.; Doblas, S.; Saunders, D.; Cranford, R.; Pearson, J.; Oblander, J.; Smith, N.; Kotake, Y.; Floyd, R. A.; Towner, R. A. Visualization of the protective ability of a free radical trapping compound against rat C6 and F98 gliomas with diffusion tensor fiber tractography. J. Magn. Reson. Imaging 28:574-587.
160. Inanami O., and Kuwabara M. alpha-Phenyl N-tert-butyl nitrone (PBN) increases the cortical cerebral blood flow by inhibiting the breakdown of nitric oxide in anesthetized rats. Free Radic. Res. 23 (1995) 33-39
161. Yamane H., Nakai Y., Takayama M., Iguchi H., Nakagawa T., and Kojima A. Appearance of free radicals in the guinea pig inner ear after noise-induced acoustic trauma. Eur. Arch. Otorhinolaryngol. 252 (1995) 504-508
162. Seidman M.D., Shivapuja B.G., and Quirk W.S. The protective effects of allopurinol and superoxide dismutase on noise-induced cochlear damage. Otolaryngol. Head Neck Surg. 109 (1993) 1052-1056
163. Hu B.H., Zheng X.Y., McFadden S.L., Kopke R.D., and Henderson D. R-phenylisopropyladenosine attenuates noise-induced hearing loss in the chinchilla. Hear. Res. 113 (1997) 198-206
164. Jacono A.A., Hu B., Kopke R.D., Henderson D., Van De Water T.R., and Steinman H.M. Changes in cochlear antioxidant enzyme activity after sound conditioning and noise exposure in the chinchilla. Hear. Res. 117 (1998) 31-38
165. Kopke R., Allen K.A., Henderson D., Hoffer M., Frenz D., and Van de W.T. A radical demise: toxins and trauma share common pathways in hair cell death. Ann. N. Y. Acad. Sci. 884 (1999) 171-191
166. Evans P., and Halliwell B. Free radicals and hearing: cause, consequence, and criteria. Ann. N. Y. Acad. Sci. 884 (1999) 19-40
167. Henderson D., Bielefeld E.C., Harris K.C., and Hu B.H. The role of oxidative stress in noise-induced hearing loss. Ear Hear. 27 (2006) 1-19
168. Ohlemiller K.K., Wright J.S., and Dugan L.L. Early elevation of cochlear reactive oxygen species following noise exposure. Audiol. Neurootol. 4 (1999) 229-236
169. Ohinata Y., Miller J.M., Altschuler R.A., and Schacht J. Intense noise induces formation of vasoactive lipid peroxidation products in the cochlea. Brain Res. 878 (2000) 163-173
170. Yamashita D., Jiang H.Y., Schacht J., and Miller J.M. Delayed production of free radicals following noise exposure. Brain Res. 1019 (2004) 201-209
171. Kopke R.D., Coleman J.K., Liu J., Campbell K.C., and Riffenburgh R.H. Candidate's thesis: enhancing intrinsic cochlear stress defenses to reduce noise-induced hearing loss. Laryngoscope 112 (2002) 1515-1532
172. Kopke R., Bielefeld E., Liu J., Zheng J., Jackson R., Henderson D., and Coleman J.K. Prevention of impulse noise-induced hearing loss with antioxidants. Acta Otolaryngol. 125 (2005) 235-243
173. Shi X., and Nuttall A.L. Upregulated iNOS and oxidative damage to the cochlear stria vascularis due to noise stress. Brain Res. 967 (2003) 1-10
174. Shi X., Dai C., and Nuttall A.L. Altered expression of inducible nitric oxide synthase (iNOS) in the cochlea. Hear. Res. 177 (2003) 43-52
175. Wang J., Pignol B., Chabrier P.E., Saido T., Lloyd R., Tang Y., Lenoir M., and Puel J.L. A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma. Neuropharmacology 52 (2007) 1426-1437
176. Cheng A.G., Cunningham L.L., and Rubel E.W. Mechanisms of hair cell death and protection. Curr. Opin. Otolaryngol. Head Neck Surg. 13 (2005) 343-348
177. Kopke R.D., Weisskopf P.A., Boone J.L., Jackson R.L., Wester D.C., Hoffer M.E., Lambert D.C., Charon C.C., Ding D.L., and McBride D. Reduction of noise-induced hearing loss using L-NAC and salicylate in the chinchilla. Hear. Res. 149 (2000) 138-146
178. Kopke R.D., Jackson R.L., Coleman J.K., Liu J., Bielefeld E.C., and Balough B.J. NAC for noise: from the bench top to the clinic. Hear. Res. 226 (2007) 114-125
179. Hight N.G., McFadden S.L., Henderson D., Burkard R.F., and Nicotera T. Noise-induced hearing loss in chinchillas pre-treated with glutathione monoethylester and R-PIA. Hear. Res. 179 (2003) 21-32
180. Fechter L.D., Gearhart C., and Shirwany N.A. Acrylonitrile potentiates noise-induced hearing loss in rat. J. Assoc. Res. Otolaryngol. 5 (2004) 90-98
181. Fechter L.D., Klis S.F., Shirwany N.A., Moore T.G., and Rao D.B. Acrylonitrile produces transient cochlear function loss and potentiates permanent noise-induced hearing loss. Toxicol. Sci. 75 (2003) 117-123
182. Rao D., and Fechter L.D. Protective effects of phenyl-N-tert-butylnitrone on the potentiation of noise-induced hearing loss by carbon monoxide. Toxicol. Appl. Pharmacol. 167 (2000) 125-131
183. Pouyatos B., Gearhart C.A., and Fechter L.D. Acrylonitrile potentiates hearing loss and cochlear damage induced by moderate noise exposure in rats. Toxicol. Appl. Pharmacol. 204 (2005) 46-56
184. Choi C.H., Chen K., Vasquez-Weldon A., Jackson R.L., Floyd R.A., and Kopke R.D. Effectiveness of 4-hydroxy phenyl N-tert-butylnitrone (4-OHPBN) alone and in combination with other antioxidant drugs in the treatment of acute acoustic trauma in chinchilla. Free Radic. Biol. Med. 44 (2008) 1772-1784
185. Floyd R.A. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc. Soc. Exp. Biol. Med. 222 (1999) 236-245
186. Mak I.T., and Weglicki W.B. Potent antioxidant properties of 4-hydroxyl-propranolol. J. Pharmacol. Exp. Ther. 308 (2004) 85-90
187. Mak I.T., Chmielinska J.J., Nedelec L., Torres A., and Weglicki W.B. d-Propranolol attenuates lysosomal iron accumulation and oxidative injury in endothelial cells. J. Pharmacol. Exp. Ther. 317 (2006) 522-528
188. Kramer J.H., Murthi S.B., Wise R.M., Mak I.T., and Weglicki W.B. Antioxidant and lysosomotropic properties of acute d-propranolol underlie its cardioprotection of postischemic hearts from moderate iron-overloaded rats. Exp. Biol. Med. (Maywood) 231 (2006) 473-484
189. Coleman J.K., Kopke R.D., Liu J., Ge X., Harper E.A., Jones G.E., Cater T.L., and Jackson R.L. Pharmacological rescue of noise induced hearing loss using N-acetylcysteine and acetyl-l-carnitine. Hear. Res. 226 (2007) 104-113