Neurotoxic lipid peroxidation species formed by ischemic stroke increase injury.

Zeiger SL, Musiek ES, Zanoni G, Vidari G, Morrow JD, Milne GJ, McLaughlin B
Free Radic Biol Med. 2009 47 (10): 1422-31

PMID: 19699297 · PMCID: PMC2767385 · DOI:10.1016/j.freeradbiomed.2009.08.011

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.

MeSH Terms (17)

Animals Calcium Cells, Cultured Cytochromes c Dose-Response Relationship, Drug Humans Lipid Peroxidation Mass Spectrometry Mitochondria Neurons Prostaglandins A Rats Rats, Sprague-Dawley Reactive Oxygen Species Reperfusion Injury Stroke Time Factors

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