Neurotoxic lipid peroxidation species formed by ischemic stroke increase injury.
Stroke is the third leading cause of death in the United States, yet no neuroprotective agents for treatment are clinically available. There is a pressing need to understand the signaling molecules that mediate ischemic cell death and identify novel neuroprotective targets. Cyclopentenone isoprostanes (IsoPs), formed after free radical-mediated peroxidation of arachidonic acid, are used as markers of stress, but their bioactivity is poorly understood. We have recently shown that 15-A(2t)-IsoP is a potent neurotoxin in vitro and increases the free radical burden in neurons. In this work, we demonstrate that 15-A(2t)-IsoP is abundantly produced in stroke-infarcted human cortical tissue. Using primary neuronal cultures we found that minimally toxic exposure to 15-A(2t)-IsoP does not alter ATP content, but in combination with oxygen glucose deprivation resulted in a significant hyperpolarization of the mitochondrial membrane and dramatically increased neuronal cell death. In the presence of Ca(2+), 15-A(2t)-IsoP led to a rapid induction of the permeability transition pore and release of cytochrome c. Taken with our previous work, these data support a model in which ischemia causes generation of reactive oxygen species, calcium influx, lipid peroxidation, and 15-A(2t)-IsoP formation. These factors combine to enhance opening of the permeability transition pore leading to cell death subsequent to mitochondrial cytochrome c release. These data are the first documentation of significant 15-A(2t)-IsoP formation after acute ischemic stroke and suggest that the addition of 15-A(2t)-IsoP to in vitro models of ischemia may help to more fully recapitulate stroke injury.
Zeiger
Stephanie L H
SL
Department of Neurology, Vanderbilt University, Nashville, TN 37232, USA.
Musiek
Erik S
ES
Zanoni
Giuseppe
G
Vidari
Giovanni
G
Morrow
Jason D
JD
Milne
Ginger J
GJ
McLaughlin
BethAnn
B
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015227:Lipid Peroxidation; D013058:Mass Spectrometry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011454:Prostaglandins A / Q000096:biosynthesis* / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism*; D013997:Time Factors
C117466:8-isoprostaglandin A2; D011454:Prostaglandins A; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D002118:Calcium
Biochimie. 2002 Feb-Mar;84(2-3):241-50
12022955
Cardiovasc Res. 2004 Feb 15;61(3):372-85
14962470
J Biol Chem. 1981 Aug 25;256(16):8652-7
7263675
Chem Phys Lipids. 2004 Mar;128(1-2):117-24
15037157
Biochem J. 2002 Oct 15;367(Pt 2):541-8
12149099
J Cereb Blood Flow Metab. 2001 Jan;21(1):2-14
11149664
J Neurochem. 2006 Jun;97(5):1301-13
16638022
Stroke. 1998 Mar;29(3):705-18
9506616
Biochim Biophys Acta. 2005 Jan 7;1706(1-2):40-52
15620364
Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):715-20
12522260
Cell. 1997 Nov 28;91(5):627-37
9393856
J Neurosci. 1999 Nov 15;19(22):RC39
10559429
Annu Rev Physiol. 2007;69:51-67
17007587
Free Radic Biol Med. 1989;6(3):303-13
2663663
Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H39-46
12933349
Cell Physiol Biochem. 2007;20(1-4):1-22
17595511
Ann N Y Acad Sci. 2001 Jun;939:11-22
11462762
Genes Dev. 2005 Jun 1;19(11):1294-305
15901672
Stroke. 1999 Feb;30(2):433-40
9933284
Curr Drug Targets Inflamm Allergy. 2002 Jun;1(2):151-66
14561197
Biophys J. 1988 May;53(5):785-94
3390520
Science. 1993 Oct 29;262(5134):689-95
7901908
Arterioscler Thromb Vasc Biol. 2003 Mar 1;23(3):368-70
12639824
Cell Mol Life Sci. 2002 May;59(5):808-20
12088281
Stroke. 1997 Aug;28(8):1557-63
9259748
Rev Physiol Biochem Pharmacol. 1985;102:1-72
2863864
Clin Chem. 2005 Jan;51(1):125-31
15514100
Neuroreport. 2000 Apr 27;11(6):1357-60
10817621
Biochim Biophys Acta. 1999 Jan 4;1436(3):550-6
9989284
J Biol Chem. 2001 Apr 13;276(15):12035-40
11134037
Mol Cell Biol. 1999 Aug;19(8):5800-10
10409766
Brain Res. 1997 Feb 7;747(2):297-303
9046005
NeuroRx. 2004 Jan;1(1):36-45
15717006
J Biol Chem. 1999 Apr 16;274(16):10863-8
10196163
J Neurochem. 2008 May;105(4):1525-35
18248613
Cell Cycle. 2007 Apr 1;6(7):807-9
17377500
Stroke. 1994 Feb;25(2):457-64; discussion 464-5
8303757
Biochem Soc Trans. 2006 Apr;34(Pt 2):232-7
16545083
Nat Cell Biol. 2006 Dec;8(12):1348-58
17115033
NeuroRx. 2004 Jan;1(1):101-10
15717010
J Biol Chem. 1997 Feb 7;272(6):3346-54
9013575
J Biol Chem. 2006 Dec 8;281(49):37391-403
17035241
Biosci Rep. 2007 Jun;27(1-3):11-21
17497220
J Physiol. 1995 Jul 1;486 ( Pt 1):1-13
7562625
J Biol Chem. 1970 Sep 25;245(18):4724-31
4393961
Br J Pharmacol. 2001 Oct;134(3):535-42
11588107
FEBS J. 2005 Jul;272(14):3593-601
16008559
Stroke. 1998 Jan;29(1):196-201; discussion 202
9445351
FEBS J. 2006 May;273(10):2077-99
16649987
Biophys J. 1989 Dec;56(6):1053-69
2611324
Free Radic Biol Med. 1998 Mar 1;24(4):624-31
9559874
Neuropharmacology. 2008 Sep;55(3):363-89
18308347
Stroke. 2008 Jan;39(1):100-4
18063832
Biochem J. 2006 Feb 15;394(Pt 1):185-95
16268779
Oncogene. 1998 Dec 24;17(25):3237-45
9916986
Chem Res Toxicol. 2002 Sep;15(9):1114-8
12230403
Cytometry. 1995 Nov 1;21(3):265-74
8582249
Brain Pathol. 2005 Apr;15(2):149-58
15912888
J Neurochem. 2007 Sep;102(5):1625-1634
17697048
Ann N Y Acad Sci. 2005 May;1042:203-9
15965064
FEBS Lett. 2000 Jun 23;475(3):267-72
10869569
Proc Natl Acad Sci U S A. 1990 Dec;87(23):9383-7
2123555
J Biol Chem. 2003 Sep 12;278(37):34757-63
12815061
Adv Exp Med Biol. 2002;513:455-73
12575832
Physiol Rev. 1999 Oct;79(4):1431-568
10508238