title: Antioxidant therapies in traumatic brain and spinal cord injury.
abstract: Free radical formation and oxidative damage have been extensively investigated and validated as important contributors to the pathophysiology of acute central nervous system injury. The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following injury occurring within minutes of mechanical impact. A key component in this event is peroxynitrite-induced lipid peroxidation. As discussed in this review, peroxynitrite formation and lipid peroxidation irreversibly damages neuronal membrane lipids and protein function, which results in subsequent disruptions in ion homeostasis, glutamate-mediated excitotoxicity, mitochondrial respiratory failure and microvascular damage. Antioxidant approaches include the inhibition and/or scavenging of superoxide, peroxynitrite, or carbonyl compounds, the inhibition of lipid peroxidation and the targeting of the endogenous antioxidant defense system. This review covers the preclinical and clinical literature supporting the role of ROS and RNS and their derived oxygen free radicals in the secondary injury response following acute traumatic brain injury (TBI) and spinal cord injury (SCI) and reviews the past and current trends in the development of antioxidant therapeutic strategies. Combinatorial treatment with the suggested mechanistically complementary antioxidants will also be discussed as a promising neuroprotective approach in TBI and SCI therapeutic research. This article is part of a Special Issue entitled: Antioxidants and antioxidant treatment in disease.
authors.affiliation: Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Bains
authors.forename: Edward D
authors.initials: ED
authors.lastname: Hall
mesh_terms: D000975:Antioxidants / Q000627:therapeutic use*; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species
references.citation: Neurosurgery. 2000 Jan;46(1):169-77
references.pmid: 10626947
references.citation: J Neurosurg. 1998 Oct;89(4):519-25
references.pmid: 9761043
references.citation: Crit Care Med. 2009 Jan;37(1 Suppl):S129-35
references.pmid: 19104212
references.citation: J Neurochem. 2011 May;117(3):579-88
references.pmid: 21361959
references.citation: Spine (Phila Pa 1976). 2000 Apr 1;25(7):769-75
references.pmid: 10751286
references.citation: Neurotherapeutics. 2011 Apr;8(2):152-67
references.pmid: 21424941
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:89-116
references.pmid: 16968214
references.citation: Chem Res Toxicol. 2000 Apr;13(4):294-300
references.pmid: 10775330
references.citation: Neurochem Res. 2005 Mar;30(3):291-5
references.pmid: 16018572
references.citation: Acta Neurochir Suppl. 2004;89:101-7
references.pmid: 15335108
references.citation: Pharmacol Ther. 2010 May;126(2):119-45
references.pmid: 20153367
references.citation: J Neurochem. 2008 Nov;107(3):712-21
references.pmid: 18710419
references.citation: Injury. 2011 Jul;42(7):714-8
references.pmid: 21466884
references.citation: Mol Cell Biochem. 2007 Jan;294(1-2):137-44
references.pmid: 16924419
references.citation: J Neurotrauma. 2007 Jun;24(6):991-9
references.pmid: 17600515
references.citation: Free Radic Res. 2009 Jun;43(6):604-12
references.pmid: 19513907
references.citation: J Vasc Surg. 2004 Jul;40(1):138-45
references.pmid: 15218474
references.citation: J Neurosurg. 1982 Aug;57(2):247-53
references.pmid: 6283042
references.citation: Free Radic Biol Med. 2000 Aug;29(3-4):343-8
references.pmid: 11035263
references.citation: J Pharmacol Exp Ther. 1979 Jul;210(1):112-5
references.pmid: 36476
references.citation: J Neurosurg. 1995 Nov;83(5):942
references.pmid: 7472573
references.citation: Adv Pharmacol. 1994;28:221-68
references.pmid: 8080818
references.citation: J Neurosurg. 1992 Jan;76(1):23-31
references.pmid: 1727165
references.citation: Cent Nerv Syst Trauma. 1986 Fall;3(4):257-63
references.pmid: 3107844
references.citation: J Neurosurg. 2000 Jul;93(1 Suppl):77-84
references.pmid: 10879762
references.citation: J Spinal Disord. 2000 Jun;13(3):185-99
references.pmid: 10872756
references.citation: Free Radic Biol Med. 2008 Nov 15;45(10):1457-67
references.pmid: 18801426
references.citation: Drug Metab Rev. 2006;38(4):769-89
references.pmid: 17145701
references.citation: J Neurosurg. 1998 May;88(5):874-83
references.pmid: 9576257
references.citation: Brain Res. 2011 Feb 16;1374:100-9
references.pmid: 21111721
references.citation: Neurochem Res. 1997 Oct;22(10):1231-6
references.pmid: 9342727
references.citation: J Neurochem. 1997 Jun;68(6):2469-76
references.pmid: 9166741
references.citation: Spinal Cord. 2000 May;38(5):273-86
references.pmid: 10822400
references.citation: Chem Res Toxicol. 1998 Jul;11(7):720-1
references.pmid: 9671533
references.citation: NeuroRx. 2004 Jan;1(1):80-100
references.pmid: 15717009
references.citation: Mediators Inflamm. 2010;2010:238321
references.pmid: 20862369
references.citation: Res Commun Chem Pathol Pharmacol. 1994 Mar;83(3):243-54
references.pmid: 8008974
references.citation: FASEB J. 2004 Jan;18(1):149-51
references.pmid: 14597558
references.citation: J Neurosurg. 1982 Jan;56(1):106-13
references.pmid: 7054403
references.citation: J Neurotrauma. 1988;5(1):81-9
references.pmid: 3057217
references.citation: Spinal Cord. 2007 Mar;45(3):190-205
references.pmid: 17179973
references.citation: J Neurochem. 2009 Dec;111(6):1348-56
references.pmid: 19780896
references.citation: Life Sci. 1998;62(10):853-9
references.pmid: 9496707
references.citation: Acta Neurochir Suppl. 1998;71:120-2
references.pmid: 9779162
references.citation: Brain Res. 1997 Mar 21;751(2):336-8
references.pmid: 9099824
references.citation: J Neurosurg. 2000 Jul;93(1 Suppl):1-7
references.pmid: 10879751
references.citation: Acta Pharmacol Sin. 2006 Oct;27(10):1317-25
references.pmid: 17007738
references.citation: J Neurosurg. 1986 May;64(5):803-7
references.pmid: 3009736
references.citation: Neurosci Lett. 2009 Aug 28;460(2):103-7
references.pmid: 19515491
references.citation: J Neurosurg. 2003 Jan;98(1):32-6
references.pmid: 12546349
references.citation: Antioxid Redox Signal. 2009 Nov;11(11):2851-97
references.pmid: 19432534
references.citation: Spine (Phila Pa 1976). 2001 Dec 15;26(24 Suppl):S56-7
references.pmid: 11805611
references.citation: N Engl J Med. 1990 May 17;322(20):1405-11
references.pmid: 2278545
references.citation: J Neurotrauma. 2010 Jul;27(7):1311-20
references.pmid: 20392143
references.citation: Horm Metab Res. 1997 Aug;29(8):363-72
references.pmid: 9288572
references.citation: Acta Pharmacol Sin. 2010 Nov;31(11):1421-30
references.pmid: 20953205
references.citation: J Pineal Res. 2009 Sep;47(2):134-142
references.pmid: 19627458
references.citation: Neurosci Lett. 2005 Sep 16;385(3):234-9
references.pmid: 15970378
references.citation: Clin Chem. 1995 Dec;41(12 Pt 2):1819-28
references.pmid: 7497639
references.citation: Acta Neurochir (Wien). 2001;143(1):73-81
references.pmid: 11345721
references.citation: J Neurosurg. 1988 Oct;69(4):562-7
references.pmid: 3418389
references.citation: J Med Chem. 1998 Aug 27;41(18):3477-92
references.pmid: 9719601
references.citation: J Neurotrauma. 2012 Mar 20;29(5):936-45
references.pmid: 21806470
references.citation: Biochem Pharmacol. 1996 Feb 23;51(4):471-6
references.pmid: 8619892
references.citation: Exp Neurol. 2007 May;205(1):154-65
references.pmid: 17349624
references.citation: Neurotherapeutics. 2010 Jan;7(1):51-61
references.pmid: 20129497
references.citation: Neuroscience. 2003;116(1):59-70
references.pmid: 12535938
references.citation: J Cereb Blood Flow Metab. 2008 Jun;28(6):1114-26
references.pmid: 18319733
references.citation: J Neurosci Res. 2011 Apr;89(4):515-23
references.pmid: 21259333
references.citation: Neuron. 1990 Aug;5(2):121-6
references.pmid: 2166544
references.citation: Ann N Y Acad Sci. 1999;890:462-8
references.pmid: 10668450
references.citation: J Neurochem. 2008 Feb;104(3):708-18
references.pmid: 17995940
references.citation: Lipids. 1977 Nov;12(11):945-50
references.pmid: 927047
references.citation: Chin J Traumatol. 2004 Aug;7(4):229-32
references.pmid: 15294102
references.citation: Ann N Y Acad Sci. 1994 Nov 17;738:15-24
references.pmid: 7832425
references.citation: J Neurotrauma. 2009 Aug;26(8):1369-78
references.pmid: 19419247
references.citation: Exp Neurol. 1981 Jul;73(1):321-4
references.pmid: 7250287
references.citation: Neuroscience. 2004;126(2):285-95
references.pmid: 15207346
references.citation: Chem Res Toxicol. 1999 Jun;12(6):526-34
references.pmid: 10368316
references.citation: J Neurochem. 1993 Feb;60(2):588-94
references.pmid: 8380437
references.citation: Neurosci Lett. 2011 Jan 13;488(1):60-4
references.pmid: 21056621
references.citation: J Pharmacol Exp Ther. 1987 Jul;242(1):137-42
references.pmid: 3039107
references.citation: J Neurosurg. 1982 Nov;57(5):667-73
references.pmid: 7131067
references.citation: J Neurotrauma. 1991 Fall;8(3):187-92
references.pmid: 1803027
references.citation: Chem Res Toxicol. 1996 Jul-Aug;9(5):836-44
references.pmid: 8828918
references.citation: J Neurosurg. 1986 Jun;64(6):951-61
references.pmid: 3084721
references.citation: Acta Pharmacol Sin. 2003 Jul;24(7):703-10
references.pmid: 12852839
references.citation: J Neurosci. 2003 Apr 15;23(8):3394-406
references.pmid: 12716947
references.citation: Neurosci Lett. 2007 Jun 13;420(2):133-7
references.pmid: 17531385
references.citation: J Neurochem. 1996 Jan;66(1):355-61
references.pmid: 8522975
references.citation: J Cereb Blood Flow Metab. 2005 Jun;25(6):673-84
references.pmid: 15716856
references.citation: Eur J Pharmacol. 1998 Jul 17;353(1):53-7
references.pmid: 9721039
references.citation: J Neurosurg. 1992 Jan;76(1):13-22
references.pmid: 1727150
references.citation: J Neurochem. 2007 Feb;100(3):639-49
references.pmid: 17181549
references.citation: J Neurotrauma. 2004 Jan;21(1):9-20
references.pmid: 14987461
references.citation: Free Radic Biol Med. 1998 Aug;25(3):298-304
references.pmid: 9680175
references.citation: J Pharmacol Exp Ther. 1978 Aug;206(2):361-70
references.pmid: 210274
references.citation: J Pineal Res. 2007 Sep;43(2):140-53
references.pmid: 17645692
references.citation: J Neurosci Res. 2007 Aug 1;85(10):2216-23
references.pmid: 17510982
references.citation: J Neurosurg. 1993 Mar;78(3):375-82
references.pmid: 8433137
references.citation: J Pineal Res. 2010 Apr;48(3):270-281
references.pmid: 20210855
references.citation: Physiol Res. 2005;54(6):631-7
references.pmid: 15720160
references.citation: J Neurotrauma. 2005 Oct;22(10):1123-33
references.pmid: 16238488
references.citation: Biochem Biophys Res Commun. 1998 Oct 9;251(1):83-7
references.pmid: 9790911
references.citation: J Neurotrauma. 1994 Aug;11(4):393-404
references.pmid: 7837280
references.citation: Spine (Phila Pa 1976). 2001 Dec 15;26(24 Suppl):S55
references.pmid: 11805610
references.citation: Spinal Cord. 2007 Mar;45(3):206-21
references.pmid: 17179972
references.citation: Surg Neurol. 2005 Oct;64(4):355-61
references.pmid: 16231427
references.citation: J Neurotrauma. 2004 Oct;21(10):1405-14
references.pmid: 15672631
references.citation: Surg Neurol. 1997 Jun;47(6):575-81; discussion 581-2
references.pmid: 9167783
references.citation: JAMA. 1984 Jan 6;251(1):45-52
references.pmid: 6361287
references.citation: Ann Fr Anesth Reanim. 1998;17(2):114-22
references.pmid: 9750706
references.citation: J Neurosci Res. 2003 Jan 15;71(2):220-7
references.pmid: 12503084
references.citation: JAMA. 1997 May 28;277(20):1597-604
references.pmid: 9168289
references.citation: Neurosci Lett. 2008 Jan 31;431(2):150-4
references.pmid: 18162315
references.citation: Neuroscience. 2002;115(3):839-49
references.pmid: 12435422
references.citation: Spinal Cord. 2007 Mar;45(3):222-31
references.pmid: 17179971
references.citation: J Neurosurg. 1984 Jul;61(1):124-30
references.pmid: 6374068
references.citation: J Neurosci Methods. 1997 Oct 3;76(2):115-22
references.pmid: 9350962
references.citation: J Neurosurg. 1982 Jun;56(6):838-44
references.pmid: 6281401
references.citation: J Neurosurg. 1998 Nov;89(5):699-706
references.pmid: 9817404
references.citation: J Cereb Blood Flow Metab. 2006 Nov;26(11):1407-18
references.pmid: 16538231
references.citation: Surg Neurol. 1982 Nov;18(5):320-7
references.pmid: 7179094
references.citation: J Neurosurg. 1985 Nov;63(5):704-13
references.pmid: 3903070
references.citation: J Neurotrauma. 1999 Oct;16(10):865-77
references.pmid: 10547096
references.citation: Spinal Cord. 2007 Mar;45(3):232-42
references.pmid: 17179970
references.citation: Biochem Pharmacol. 1993 Aug 3;46(3):525-34
references.pmid: 8394084
references.citation: Free Radic Biol Med. 1998 Jan 15;24(2):332-40
references.pmid: 9433909
references.citation: J Neurochem. 2010 Jul;114(1):271-80
references.pmid: 20403083
references.citation: J Neurosurg. 1993 Oct;79(4):500-7
references.pmid: 8410217
references.citation: J Surg Res. 2011 Sep;170(1):e105-15
references.pmid: 21764072
references.citation: Exp Neurol. 2006 Sep;201(1):253-65
references.pmid: 16814284