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: Stephanie L H Zeiger, Erik S Musiek, Giuseppe Zanoni, Giovanni Vidari, Jason D Morrow, Ginger J Milne, BethAnn McLaughlin
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 47 Issue 10 Pg. 1422-31 (Nov 15 2009) ISSN: 1873-4596 [Electronic] United States
• PMID: 19699297 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 8-isoprostaglandin A2
• Prostaglandins A
• Reactive Oxygen Species
• Cytochromes c
• Calcium

Topics

• Animals
• Calcium (pharmacology)
• Cells, Cultured
• Cytochromes c (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Humans
• Lipid Peroxidation
• Mass Spectrometry
• Mitochondria (drug effects, metabolism)
• Neurons (cytology, drug effects, metabolism)
• Prostaglandins A (biosynthesis, chemistry, toxicity)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Reperfusion Injury (metabolism)
• Stroke (metabolism)
• Time Factors