Inhibition of cytosolic phospholipase A2 alpha protects against focal ischemic brain damage in mice

Abstract

It is postulated that inhibition of cytosolic phospholipase A2 alpha (cPLA2α) can reduce severity of stroke injury. This is supported by the finding that cPLA2α-deficient mice are partially protected from transient, focal cerebral ischemia. The object of this study was to determine the effect of cPLA2α 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 72h 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 72h 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 PLA2 activity. These results are the first to demonstrate a therapeutic effect of cPLA2α inhibition on ischemia and reperfusion injury and define a therapeutic time window. cPLA2α activity augments injury in the acute and delayed phases of cerebral ischemia and reperfusion injury. We conclude that cPLA2α inhibition may be clinically useful if started before initiation of cerebral ischemia.