title: Neurotoxic lipid peroxidation species formed by ischemic stroke increase injury.
abstract: 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.
authors.affiliation: Department of Neurology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Stephanie L H
authors.initials: SL
authors.lastname: Zeiger
authors.forename: Erik S
authors.initials: ES
authors.lastname: Musiek
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zanoni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vidari
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Ginger J
authors.initials: GJ
authors.lastname: Milne
authors.forename: BethAnn
authors.initials: B
authors.lastname: McLaughlin
mesh_terms: 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
chemical_list: C117466:8-isoprostaglandin A2; D011454:Prostaglandins A; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D002118:Calcium
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