title: Nitrones as therapeutics.
abstract: Nitrones have the general chemical formula X-CH=NO-Y. They were first used to trap free radicals in chemical systems and then subsequently in biochemical systems. More recently several nitrones, including alpha-phenyl-tert-butylnitrone (PBN), have been shown to have potent biological activity in many experimental animal models. Many diseases of aging, including stroke, cancer development, Parkinson disease, and Alzheimer disease, are known to have enhanced levels of free radicals and oxidative stress. Some derivatives of PBN are significantly more potent than PBN and have undergone extensive commercial development for stroke. Recent research has shown that PBN-related nitrones also have anti-cancer activity in several experimental cancer models and have potential as therapeutics in some cancers. Also, in recent observations nitrones have been shown to act synergistically in combination with antioxidants in the prevention of acute acoustic-noise-induced hearing loss. The mechanistic basis of the potent biological activity of PBN-related nitrones is not known. Even though PBN-related nitrones do decrease oxidative stress and oxidative damage, their potent biological anti-inflammatory activity and their ability to alter cellular signaling processes cannot readily be explained by conventional notions of free radical trapping biochemistry. This review is focused on our studies and others in which the use of selected nitrones as novel therapeutics has been evaluated in experimental models in the context of free radical biochemical and cellular processes considered important in pathologic conditions and age-related diseases.
authors.affiliation: Experimental Therapeutics Research Program, Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. robert-floyd@omrf.org
authors.forename: Robert A
authors.initials: RA
authors.lastname: Floyd
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kopke
authors.forename: Chul-Hee
authors.initials: CH
authors.lastname: Choi
authors.forename: Steven B
authors.initials: SB
authors.lastname: Foster
authors.forename: Sabrina
authors.initials: S
authors.lastname: Doblas
authors.forename: Rheal A
authors.initials: RA
authors.lastname: Towner
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D034381:Hearing Loss / Q000188:drug therapy; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D009589:Nitrogen Oxides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D009589:Nitrogen Oxides; C015388:nitrones
references.citation: Methods Enzymol. 2005;396:535-41
references.pmid: 16291260
references.citation: Cancer. 2003 Mar 1;97(5):1358-63
references.pmid: 12599246
references.citation: Nat Med. 1999 May;5(5):582-5
references.pmid: 10229238
references.citation: Otolaryngol Head Neck Surg. 1993 Dec;109(6):1052-6
references.pmid: 8265189
references.citation: Brain Res. 2003 May 16;972(1-2):119-26
references.pmid: 12711084
references.citation: Brain Pathol. 2008 Jul;18(3):443-54
references.pmid: 18371175
references.citation: J Exp Med. 1993 Jun 1;177(6):1779-84
references.pmid: 7684434
references.citation: Ann N Y Acad Sci. 1999 Nov 28;884:171-91
references.pmid: 10842593
references.citation: Circ Shock. 1989 Dec;29(4):329-34
references.pmid: 2688966
references.citation: Laryngoscope. 2002 Sep;112(9):1515-32
references.pmid: 12352659
references.citation: Circ Res. 1989 Sep;65(3):607-22
references.pmid: 2548761
references.citation: Stroke. 2006 Oct;37(10):2644-7
references.pmid: 16946150
references.citation: Neurosci Lett. 1996 Mar 1;205(3):181-4
references.pmid: 8852588
references.citation: J Pharmacol Exp Ther. 2004 Jan;308(1):85-90
references.pmid: 14569064
references.citation: J Biol Chem. 2000 Apr 14;275(15):10954-61
references.pmid: 10753895
references.citation: FEBS Lett. 1991 Mar 11;280(1):17-20
references.pmid: 1849092
references.citation: Toxicol Sci. 2003 Sep;75(1):117-23
references.pmid: 12832658
references.citation: J Biol Chem. 1999 Jun 11;274(24):17325-33
references.pmid: 10358093
references.citation: J Biol Chem. 1983 Mar 25;258(6):3855-8
references.pmid: 6300059
references.citation: Neurosci Lett. 2000 Jan 7;278(1-2):25-8
references.pmid: 10643792
references.citation: Stroke. 2007 May;38(5):1515-8
references.pmid: 17395871
references.citation: Ann Neurol. 2007 May;61(5):396-402
references.pmid: 17420989
references.citation: Br J Pharmacol. 2008 Mar;153 Suppl 1:S325-38
references.pmid: 18059324
references.citation: J Cereb Blood Flow Metab. 2001 Apr;21(4):344-50
references.pmid: 11323520
references.citation: Ann N Y Acad Sci. 2002 Apr;959:321-9
references.pmid: 11976206
references.citation: Biochim Biophys Acta. 1998 Nov 19;1448(1):77-84
references.pmid: 9824673
references.citation: J Clin Pharmacol. 2007 Feb;47(2):264-72
references.pmid: 17244778
references.citation: J Neurosci. 2003 Jul 9;23(14):6050-7
references.pmid: 12853423
references.citation: Biochem Biophys Res Commun. 1975 Jan 2;64(3):803-7
references.pmid: 167757
references.citation: Endocrinology. 2003 Jul;144(7):2829-35
references.pmid: 12810537
references.citation: J Biol Chem. 2004 Mar 19;279(12):11600-7
references.pmid: 14699100
references.citation: Biochem Biophys Res Commun. 1995 Oct 4;215(1):114-21
references.pmid: 7575577
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11996-2001
references.pmid: 8876251
references.citation: Arch Biochem Biophys. 1986 Jan;244(1):156-60
references.pmid: 3004337
references.citation: Ann N Y Acad Sci. 1999 Nov 28;884:19-40
references.pmid: 10842581
references.citation: Stroke. 2008 Apr;39(4):1389-91
references.pmid: 18309145
references.citation: Acta Otolaryngol. 2005 Mar;125(3):235-43
references.pmid: 15966690
references.citation: Brain Res. 2002 Nov 15;955(1-2):229-35
references.pmid: 12419541
references.citation: Chem Biol Interact. 1986 Nov;60(2):115-27
references.pmid: 3024853
references.citation: Biosci Biotechnol Biochem. 1998 Apr;62(4):792-4
references.pmid: 9614711
references.citation: Exp Biol Med (Maywood). 2006 Apr;231(4):473-84
references.pmid: 16565443
references.citation: Arch Biochem Biophys. 1999 May 1;365(1):71-4
references.pmid: 10222040
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2695-9
references.pmid: 12594332
references.citation: Fundam Clin Pharmacol. 2003 Aug;17(4):433-42
references.pmid: 12914545
references.citation: Biochim Biophys Acta. 1980 Jun 5;630(1):119-30
references.pmid: 6248123
references.citation: Mol Pharmacol. 2005 Sep;68(3):847-54
references.pmid: 15967877
references.citation: J Biol Chem. 1990 Jan 15;265(2):652-9
references.pmid: 2153108
references.citation: Ren Fail. 1992;14(4):467-71
references.pmid: 1461997
references.citation: Pharmacol Ther. 2003 Dec;100(3):195-214
references.pmid: 14652110
references.citation: Brain Res. 1999 Dec 11;850(1-2):63-72
references.pmid: 10629749
references.citation: Proc Soc Exp Biol Med. 1999 Dec;222(3):236-45
references.pmid: 10601882
references.citation: Hear Res. 2007 Apr;226(1-2):104-13
references.pmid: 17023129
references.citation: Free Radic Biol Med. 2000 Feb 15;28(4):597-603
references.pmid: 10719241
references.citation: Cancer Res. 2001 Jan 1;61(1):318-26
references.pmid: 11196180
references.citation: Free Radic Biol Med. 1990;8(1):3-7
references.pmid: 2323581
references.citation: J Clin Invest. 1996 Dec 1;98(11):2632-9
references.pmid: 8958228
references.citation: Brain Res. 2000 Sep 29;878(1-2):163-73
references.pmid: 10996147
references.citation: Drug Metab Dispos. 1988 Nov-Dec;16(6):799-803
references.pmid: 2907456
references.citation: Can J Physiol Pharmacol. 1987 Mar;65(3):478-82
references.pmid: 2884028
references.citation: J Neurotrauma. 2002 Oct;19(10):1139-53
references.pmid: 12427324
references.citation: J Biol Chem. 2006 Nov 10;281(45):34124-34
references.pmid: 16980304
references.citation: Am J Physiol. 1990 Dec;259(6 Pt 2):H1901-11
references.pmid: 2260714
references.citation: Free Radic Res Commun. 1990;9(3-6):317-23
references.pmid: 2387499
references.citation: Aging Cell. 2006 Feb;5(1):51-7
references.pmid: 16441843
references.citation: N Engl J Med. 2007 Aug 9;357(6):562-71
references.pmid: 17687131
references.citation: Brain Res. 2003 Mar 28;967(1-2):1-10
references.pmid: 12650960
references.citation: Cancer Res. 2002 Mar 15;62(6):1648-53
references.pmid: 11912135
references.citation: Free Radic Res Commun. 1990;9(3-6):169-80
references.pmid: 2167254
references.citation: Invest Ophthalmol Vis Sci. 2005 Feb;46(2):427-34
references.pmid: 15671265
references.citation: J Cereb Blood Flow Metab. 2001 Nov;21(11):1259-67
references.pmid: 11702041
references.citation: J Biol Chem. 1988 Aug 15;263(23):11296-301
references.pmid: 2841325
references.citation: Hear Res. 2007 Apr;226(1-2):114-25
references.pmid: 17184943
references.citation: N Engl J Med. 2006 Feb 9;354(6):588-600
references.pmid: 16467546
references.citation: Stroke. 2003 Sep;34(9):2228-33
references.pmid: 12920263
references.citation: Br J Pharmacol. 2008 Jan;153(1):124-31
references.pmid: 17982476
references.citation: Acta Neurochir (Wien). 2001;143(1):73-81
references.pmid: 11345721
references.citation: Stroke. 2006 Dec;37(12):2970-8
references.pmid: 17068304
references.citation: J Biol Chem. 1990 Aug 15;265(23):13589-94
references.pmid: 2166035
references.citation: J Neurochem. 2002 Aug;82(4):924-34
references.pmid: 12358798
references.citation: Antioxid Redox Signal. 1999 Winter;1(4):481-99
references.pmid: 11233146
references.citation: Toxicol Appl Pharmacol. 1997 Jan;142(1):47-55
references.pmid: 9007033
references.citation: Arch Biochem Biophys. 1977 Apr 30;180(2):480-92
references.pmid: 18096
references.citation: Aging Cell. 2007 Aug;6(4):565-75
references.pmid: 17578509
references.citation: J Neurochem. 1995 May;64(5):2239-47
references.pmid: 7536809
references.citation: Biochem Biophys Res Commun. 1995 Jun 26;211(3):847-9
references.pmid: 7598714
references.citation: Arch Biochem Biophys. 1999 Mar 15;363(2):341-8
references.pmid: 10068457
references.citation: J Stroke Cerebrovasc Dis. 2002 Jan-Feb;11(1):34-42
references.pmid: 17903853
references.citation: Neurosci Lett. 1998 Jan 30;241(2-3):99-102
references.pmid: 9507930
references.citation: Eur Arch Otorhinolaryngol. 1995;252(8):504-8
references.pmid: 8719596
references.citation: Arch Biochem Biophys. 1990 Oct;282(1):65-9
references.pmid: 2171436
references.citation: FASEB J. 1990 Jun;4(9):2587-97
references.pmid: 2189775
references.citation: Adv Pharmacol. 1997;38:361-78
references.pmid: 8895816
references.citation: J Cereb Blood Flow Metab. 2008 Jan;28(1):217-9
references.pmid: 17579658
references.citation: Hepatology. 2002 Jul;36(1):81-93
references.pmid: 12085352
references.citation: Mol Cell Biochem. 2002 May-Jun;234-235(1-2):195-203
references.pmid: 12162434
references.citation: Cancer Res. 2001 Sep 1;61(17):6388-93
references.pmid: 11522631
references.citation: J Hypertens. 2003 Oct;21(10):1787-803
references.pmid: 14508181
references.citation: Hear Res. 1997 Nov;113(1-2):198-206
references.pmid: 9387999
references.citation: Toxicol Sci. 2008 May;103(1):149-57
references.pmid: 18281254
references.citation: Carcinogenesis. 1984 Oct;5(10):1367-70
references.pmid: 6488458
references.citation: Hear Res. 1998 Mar;117(1-2):31-8
references.pmid: 9557976
references.citation: Mech Ageing Dev. 2002 Apr 30;123(8):1021-31
references.pmid: 12044951
references.citation: Free Radic Biol Med. 2006 Aug 1;41(3):422-30
references.pmid: 16843823
references.citation: J Magn Reson Imaging. 2008 Sep;28(3):574-87
references.pmid: 18777527
references.citation: Free Radic Res. 2001 Nov;35(5):583-91
references.pmid: 11767416
references.citation: Science. 1996 Oct 4;274(5284):99-102
references.pmid: 8810256
references.citation: Free Radic Biol Med. 2008 Jan 1;44(1):63-72
references.pmid: 18045548
references.citation: Free Radic Biol Med. 2005 Apr 1;38(7):969-76
references.pmid: 15749393
references.citation: Science. 1991 Dec 13;254(5038):1597
references.pmid: 1684251
references.citation: Hear Res. 2003 Mar;177(1-2):43-52
references.pmid: 12618316
references.citation: J Neural Transm Suppl. 2000;(60):387-414
references.pmid: 11205157
references.citation: Neurosci Lett. 1988 May 26;88(2):233-8
references.pmid: 3380359
references.citation: J Am Chem Soc. 2007 Nov 7;129(44):13493-501
references.pmid: 17939657
references.citation: Biochim Biophys Acta. 1984 Nov 9;790(3):238-50
references.pmid: 6091763
references.citation: J Clin Pharmacol. 2007 Jul;47(7):909-14
references.pmid: 17585119
references.citation: Hear Res. 2000 Nov;149(1-2):138-46
references.pmid: 11033253
references.citation: Free Radic Res Commun. 1986;1(5):321-7
references.pmid: 3505231
references.citation: Brain Res. 2004 Sep 3;1019(1-2):201-9
references.pmid: 15306254
references.citation: Cancer Res. 1995 Feb 15;55(4):727-30
references.pmid: 7531613
references.citation: Eur J Neurosci. 2008 Mar;27(6):1475-84
references.pmid: 18364024
references.citation: Proc Natl Acad Sci U S A. 1991 May 1;88(9):3633-6
references.pmid: 1673789
references.citation: Free Radic Biol Med. 2002 Aug 1;33(3):364-9
references.pmid: 12126758
references.citation: J Pharmacol Exp Ther. 2006 May;317(2):522-8
references.pmid: 16456084
references.citation: Toxicol Appl Pharmacol. 2000 Sep 1;167(2):125-31
references.pmid: 10964763
references.citation: J Biol Chem. 1997 Dec 5;272(49):31138-48
references.pmid: 9388267
references.citation: Surgery. 1992 Aug;112(2):130-9; discussion 138-9
references.pmid: 1641756
references.citation: Free Radic Res. 2001 Apr;34(4):417-26
references.pmid: 11328677
references.citation: Stroke. 2008 Jun;39(6):1751-8
references.pmid: 18369171
references.citation: Neurosci Lett. 1990 Aug 24;116(3):315-9
references.pmid: 2243611
references.citation: Br J Pharmacol. 2008 Mar;153 Suppl 1:S112-9
references.pmid: 18311155
references.citation: J Biol Chem. 1996 Jun 28;271(26):15498-503
references.pmid: 8663160
references.citation: Nitric Oxide. 2000 Apr;4(2):157-67
references.pmid: 10835296
references.citation: J Neurochem. 2007 Jul;102(1):194-205
references.pmid: 17302912
references.citation: Brain Res. 1994 May 2;644(2):267-72
references.pmid: 8050038
references.citation: Lancet Oncol. 2001 Mar;2(3):149-56
references.pmid: 11902565
references.citation: Biochem Biophys Res Commun. 1993 Jun 30;193(3):878-85
references.pmid: 8391809
references.citation: Free Radic Biol Med. 2008 Mar 1;44(5):893-906
references.pmid: 18160050
references.citation: Drugs Aging. 2007;24(7):537-46
references.pmid: 17658905
references.citation: Free Radic Biol Med. 2008 May 1;44(9):1772-84
references.pmid: 18328271
references.citation: Cancer Sci. 2003 Jan;94(1):26-31
references.pmid: 12708470
references.citation: Cancer Res. 1998 Oct 15;58(20):4548-51
references.pmid: 9788598
references.citation: Hepatology. 2000 Oct;32(4 Pt 1):770-8
references.pmid: 11003621
references.citation: Neuropharmacology. 2007 May;52(6):1426-37
references.pmid: 17449343
references.citation: Circ Shock. 1986;19(4):429-39
references.pmid: 3742740
references.citation: Curr Opin Otolaryngol Head Neck Surg. 2005 Dec;13(6):343-8
references.pmid: 16282762
references.citation: Ear Hear. 2006 Feb;27(1):1-19
references.pmid: 16446561
references.citation: CNS Drugs. 2004;18(15):1071-84
references.pmid: 15581379
references.citation: Cancer Res. 1987 Dec 15;47(24 Pt 1):6731-40
references.pmid: 3677103
references.citation: Toxicol Appl Pharmacol. 2005 Apr 1;204(1):46-56
references.pmid: 15781293
references.citation: Audiol Neurootol. 1999 Sep-Oct;4(5):229-36
references.pmid: 10436315
references.citation: Exp Neurol. 2007 May;205(1):20-5
references.pmid: 17408618
references.citation: J Clin Invest. 1988 Aug;82(2):476-85
references.pmid: 2841353
references.citation: Free Radic Res. 1995 Jul;23(1):33-9
references.pmid: 7544190
references.citation: Free Radic Biol Med. 1997;22(5):917-22
references.pmid: 9119262
references.citation: Biochem Pharmacol. 1979 Jul 15;28(14):2231-5
references.pmid: 227403
references.citation: Free Radic Biol Med. 2000 Apr 1;28(7):1079-90
references.pmid: 10832069
references.citation: J Assoc Res Otolaryngol. 2004 Mar;5(1):90-8
references.pmid: 14669069
references.citation: Hear Res. 2003 May;179(1-2):21-32
references.pmid: 12742235
references.citation: Free Radic Biol Med. 2007 Feb 15;42(4):530-40
references.pmid: 17275685
references.citation: FEBS Lett. 1997 Apr 28;407(2):148-52
references.pmid: 9166889
references.citation: Surgery. 1998 Aug;124(2):278-83
references.pmid: 9706149
references.citation: Biochim Biophys Acta. 1978 Mar 20;539(3):402-9
references.pmid: 24480
references.citation: Aging Cell. 2008 Oct;7(5):641-50
references.pmid: 18631321
references.citation: Biochem Biophys Res Commun. 1977 Jan 10;74(1):79-84
references.pmid: 189765
references.citation: J Biol Chem. 1997 Jan 10;272(2):1402-11
references.pmid: 8995451
references.citation: Biochem Pharmacol. 1982 Feb 1;31(3):405-9
references.pmid: 7073767
references.citation: Photochem Photobiol. 1990 Aug;52(2):323-31
references.pmid: 2171003
references.citation: Proc Natl Acad Sci U S A. 1989 Jun;86(12):4695-9
references.pmid: 2543984
references.citation: Photochem Photobiol. 1978 Oct-Nov;28(4-5):857-62
references.pmid: 216035
references.citation: Nat Methods. 2006 Feb;3(2):123-7
references.pmid: 16432522
references.citation: Invest Ophthalmol Vis Sci. 2001 May;42(6):1375-9
references.pmid: 11328754