Production of leukotrienes in a model of focal cerebral ischaemia in the rat

1 The aim of this work was to evaluate the role of leukotrienes in brain da mage in vivo in a model of focal cerebral ischaemia in the rat, obtained by permanent occlusion of middle cerebral artery. 2 A significant (P<0.01) elevation of LTC4, LTD4 and LTE4 (cysteinyl-leukot rienes) levels occurred 4 h after ischaemia induction in the ipsilateral co rtices of ischaemic compared to sham-operated animals (3998<plus/minus>475 and 897 +/- 170 fmol g(-1) tissue, respectively, P<0.01). 3 The NMDA receptor antagonist MK-801 and the adenosine A(2A) receptor anta gonist SCH 58261 were administered in viro at doses known to reduce infarct size and compared with the leukotriene biosynthesis inhibitor MK-886. 4 MK-886 (0.3 and 2 mg kg(-1) i.v.) and MK-801 (3 mg kg(-1) i.p.) decreased cysteinyl-leukotriene levels (-78%, P<0.05, -100%, P<0.01; -92%. P<0.01, r espectively) 4 h after permanent occlusion of the middle cerebral artery, w hereas SCH 58261 (0.01 mg kg(-1) i.v.) had no significant effects. 5 MK-886 (2 mg kg(-1) i.v.) was also able to significantly reduce the corti cal infarct size by 30% (P < 0.05). 6 We conclude that cysteinyl-leukotriene formation is associated with NMDA receptor activation, and that it represents a neurotoxic event, the inhibit ion of which is able to reduce brain infarct area in a focal ischaemic even t.