Inhibition of cytosolic phospholipase A(2) alpha protects against focal ischemic brain damage in mice.

Abstract

It is postulated that inhibition of cytosolic phospholipase A(2) alpha (cPLA(2)α) can reduce severity of stroke injury. This is supported by the finding that cPLA(2)α-deficient mice are partially protected from transient, focal cerebral ischemia. The object of this study was to determine the effect of cPLA(2)α inhibition with arachidonyl trifluoromethyl ketone (ATK) on stroke injury in mice. Male C57BL/6 mice were subjected to 1h of focal cerebral ischemia followed by 24 or 72 h of reperfusion. Mice were treated with ATK or vehicle by intermittent intraperitoneal injection or continuous infusion via an implanted infusion pump. ATK injections 1h before and then 1 and 6h after the start of reperfusion significantly reduced infarction volumes in striatum and hemisphere after 24h of reperfusion. ATK did not reduce injury if it was not administered before onset of ischemia or was not administered after 6h of reperfusion. Intermittent doses of ATK failed to reduce infarct volume after 72 h of reperfusion. Continuous infusion with ATK throughout 72h of reperfusion significantly reduced cortical and whole hemispheric infarct volume compared to vehicle treatment. Following ischemia and reperfusion, ATK treatment significantly reduced brain PLA(2) activity. These results are the first to demonstrate a therapeutic effect of cPLA(2)α inhibition on ischemia and reperfusion injury and define a therapeutic time window. cPLA(2)α activity augments injury in the acute and delayed phases of cerebral ischemia and reperfusion injury. We conclude that cPLA(2)α inhibition may be clinically useful if started before initiation of cerebral ischemia.

• Authors: Jian Zhang, Noah Barasch, Rung-Chi Li, Adam Sapirstein
• Journal: Brain research (Brain Res) Vol. 1471 Pg. 129-37 (Aug 30 2012) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 22819928 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Arachidonic Acids
• Nitrobenzenes
• Sulfonamides
• arachidonyltrifluoromethane
• N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
• Cyclooxygenase 2
• Group IV Phospholipases A2

Topics

• Analysis of Variance
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Arachidonic Acids (therapeutic use)
• Body Temperature (drug effects)
• Brain Infarction (etiology, prevention & control)
• Brain Injuries (drug therapy, etiology, metabolism)
• Cyclooxygenase 2 (metabolism)
• Disease Models, Animal
• Functional Laterality (drug effects)
• Group IV Phospholipases A2 (antagonists & inhibitors, deficiency)
• Infarction, Middle Cerebral Artery (complications)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitrobenzenes (therapeutic use)
• Reperfusion
• Reperfusion Injury (prevention & control)
• Sulfonamides (therapeutic use)
• Time Factors