title: Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection.
abstract: Significant amounts of oxygen free radicals (oxidants) are generated during cerebral ischemia/reperfusion, and oxidative stress plays an important role in brain damage after stroke. In addition to oxidizing macromolecules, leading to cell injury, oxidants are also involved in cell death/survival signal pathways and cause mitochondrial dysfunction. Experimental data from laboratory animals that either overexpress (transgenic) or are deficient in (knock-out) antioxidant proteins, mainly superoxide dismutase, have provided strong evidence of the role of oxidative stress in ischemic brain damage. In addition to mitochondria, recent reports demonstrate that NADPH oxidase (NOX), an important pro-oxidant enzyme, is also involved in the generation of oxidants in the brain after stroke. Inhibition of NOX is neuroprotective against cerebral ischemia. We propose that superoxide dismutase and NOX activity in the brain is a major determinant for ischemic damage/repair and that these major anti- and pro-oxidant enzymes are potential endogenous molecular targets for stroke therapy.
authors.affiliation: Departments of Neurosurgery and Neurology and Neurological Sciences and Program in Neurosciences, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA 94305-5487, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Chen
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshioka
authors.forename: Gab Seok
authors.initials: GS
authors.lastname: Kim
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.forename: Nobuya
authors.initials: N
authors.lastname: Okami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakata
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Maier
authors.forename: Purnima
authors.initials: P
authors.lastname: Narasimhan
authors.forename: Christina E
authors.initials: CE
authors.lastname: Goeders
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
mesh_terms: D000818:Animals; D016923:Cell Death; D019610:Cytoprotection; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D016877:Oxidants; D013482:Superoxide Dismutase; D019255:NADPH Oxidases
references.citation: J Pharmacol Exp Ther. 2001 Feb;296(2):312-21
references.pmid: 11160612
references.citation: Free Radic Biol Med. 2005 Jul 1;39(1):71-80
references.pmid: 15925279
references.citation: J Neurosci. 1999 May 1;19(9):3414-22
references.pmid: 10212301
references.citation: Ann Neurol. 2009 May;65(5):520-30
references.pmid: 19475672
references.citation: J Neurosci. 1998 Jan 15;18(2):687-97
references.pmid: 9425011
references.citation: J Neurosci. 2000 Apr 15;20(8):2817-24
references.pmid: 10751433
references.citation: J Cereb Blood Flow Metab. 2005 Oct;25(10):1301-11
references.pmid: 15829915
references.citation: Neuroscience. 2009 Feb 6;158(3):995-1006
references.pmid: 18675321
references.citation: Cell. 1996 Nov 15;87(4):619-28
references.pmid: 8929531
references.citation: Biochim Biophys Acta. 2010 Jan;1802(1):92-9
references.pmid: 19751828
references.citation: J Cereb Blood Flow Metab. 2008 Oct;28(10):1686-96
references.pmid: 18545259
references.citation: Ann Neurol. 2006 Jun;59(6):929-38
references.pmid: 16673393
references.citation: J Biol Chem. 1998 Dec 25;273(52):35147-52
references.pmid: 9857051
references.citation: Stroke. 2005 Dec;36(12):2712-7
references.pmid: 16269636
references.citation: J Cereb Blood Flow Metab. 2005 Feb;25(2):267-80
references.pmid: 15678128
references.citation: J Clin Invest. 2007 Apr;117(4):910-8
references.pmid: 17404617
references.citation: J Neurosci. 1997 Jun 1;17(11):4180-9
references.pmid: 9151735
references.citation: Genes Dev. 2001 Nov 15;15(22):2922-33
references.pmid: 11711427
references.citation: Stroke. 1994 Jan;25(1):165-70
references.pmid: 8266365
references.citation: J Neurosci. 1999 Nov 15;19(22):RC39
references.pmid: 10559429
references.citation: J Neurosci. 2006 Jul 26;26(30):7974-83
references.pmid: 16870742
references.citation: Exp Neurol. 2004 Jun;187(2):478-86
references.pmid: 15144874
references.citation: J Cereb Blood Flow Metab. 2011 Mar;31(3):868-80
references.pmid: 20859296
references.citation: Stroke. 1997 Sep;28(9):1797-804
references.pmid: 9303028
references.citation: J Neurosci. 2005 Jul 6;25(27):6401-8
references.pmid: 16000631
references.citation: Proc Natl Acad Sci U S A. 1990 Feb;87(4):1620-4
references.pmid: 2154753
references.citation: Stroke. 1997 Nov;28(11):2252-8
references.pmid: 9368573
references.citation: J Neurosci. 2002 Jan 1;22(1):209-17
references.pmid: 11756504
references.citation: J Neurosci. 2009 May 27;29(21):7003-14
references.pmid: 19474327
references.citation: J Neurosci. 2003 Mar 1;23(5):1710-8
references.pmid: 12629175
references.citation: J Biol Chem. 2000 Nov 17;275(46):36062-6
references.pmid: 10967126
references.citation: Mol Neurobiol. 2001 Feb;23(1):1-19
references.pmid: 11642541
references.citation: J Cereb Blood Flow Metab. 2002 Jun;22(6):631-47
references.pmid: 12045661
references.citation: J Cereb Blood Flow Metab. 2001 May;21(5):557-67
references.pmid: 11333366
references.citation: Cell. 1992 Jun 26;69(7):1237-45
references.pmid: 1535557
references.citation: Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2210-5
references.pmid: 16766636
references.citation: Science. 2002 Aug 16;297(5584):1186-90
references.pmid: 12183632
references.citation: Cell. 1997 Oct 17;91(2):231-41
references.pmid: 9346240
references.citation: Proc Natl Acad Sci U S A. 1987 Nov;84(22):8044-8
references.pmid: 2960971
references.citation: Stroke. 2003 Jun;34(6):1513-8
references.pmid: 12738898
references.citation: J Cereb Blood Flow Metab. 2005 Oct;25(10):1312-24
references.pmid: 15829914
references.citation: Stroke. 2007 Nov;38(11):3000-6
references.pmid: 17916764
references.citation: Stroke. 2006 Feb;37(2):513-7
references.pmid: 16397181
references.citation: Science. 1998 Nov 13;282(5392):1318-21
references.pmid: 9812896
references.citation: Antioxid Redox Signal. 2003 Oct;5(5):647-54
references.pmid: 14580322
references.citation: N Engl J Med. 2007 Aug 9;357(6):562-71
references.pmid: 17687131
references.citation: Physiol Rev. 2007 Jan;87(1):245-313
references.pmid: 17237347
references.citation: Lancet Neurol. 2003 Jan;2(1):43-53
references.pmid: 12849300
references.citation: J Neurosci. 1998 Oct 15;18(20):8292-9
references.pmid: 9763473
references.citation: J Cereb Blood Flow Metab. 2001 Dec;21(12):1393-400
references.pmid: 11740200
references.citation: Cell. 1998 Sep 18;94(6):739-50
references.pmid: 9753321
references.citation: Nature. 2009 Apr 30;458(7242):1127-30
references.pmid: 19407794
references.citation: Stroke. 2009 Feb;40(2):618-25
references.pmid: 19095966
references.citation: Oncogene. 2008 Dec;27 Suppl 1:S71-83
references.pmid: 19641508
references.citation: J Cereb Blood Flow Metab. 2001 Jan;21(1):2-14
references.pmid: 11149664
references.citation: Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1583-96
references.pmid: 16987013
references.citation: Physiol Rev. 2002 Jan;82(1):47-95
references.pmid: 11773609
references.citation: J Cereb Blood Flow Metab. 2009 Jul;29(7):1262-72
references.pmid: 19417757
references.citation: Stroke. 1999 Sep;30(9):1962-8
references.pmid: 10471451
references.citation: Nat Rev Neurosci. 2003 May;4(5):399-415
references.pmid: 12728267
references.citation: J Neurosci. 1998 Jan 1;18(1):205-13
references.pmid: 9412501
references.citation: Stroke. 2004 May;35(5):1169-74
references.pmid: 15060315
references.citation: J Neurosci. 2004 Feb 18;24(7):1584-93
references.pmid: 14973226
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16368-73
references.pmid: 18845684
references.citation: J Neurosci. 2009 Nov 25;29(47):14779-89
references.pmid: 19940173
references.citation: Nat Neurosci. 2009 Jul;12(7):857-63
references.pmid: 19503084
references.citation: Neuroscience. 2008 Jun 23;154(2):556-62
references.pmid: 18511205
references.citation: J Neurosci. 2007 Jan 31;27(5):1129-38
references.pmid: 17267568
references.citation: Stroke. 2007 Mar;38(3):1044-9
references.pmid: 17272778
references.citation: Stroke. 1996 Jun;27(6):1124-9
references.pmid: 8650725
references.citation: J Neurosci. 2001 Oct 1;21(19):7724-32
references.pmid: 11567062
references.citation: Brain Res. 2006 May 23;1090(1):182-9
references.pmid: 16650838
references.citation: Cell. 1997 Feb 21;88(4):435-7
references.pmid: 9038334
references.citation: Ann Neurol. 2008 Dec;64(6):654-63
references.pmid: 19107988
references.citation: Neuroreport. 1993 Dec 13;5(3):293-6
references.pmid: 8298091
references.citation: J Cereb Blood Flow Metab. 2007 Apr;27(4):764-75
references.pmid: 16868554
references.citation: J Cereb Blood Flow Metab. 2006 Dec;26(12):1479-89
references.pmid: 16538228
references.citation: Stroke. 2009 Apr;40(4):1467-73
references.pmid: 19228841
references.citation: Physiol Rev. 1999 Oct;79(4):1431-568
references.pmid: 10508238