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

The aim of this work was to evaluate the role of leukotrienes in brain damage in vivo in a model of focal cerebral ischaemia in the rat, obtained by permanent occlusion of middle cerebral artery. A significant ( P <0.01) elevation of LTC 4 , LTD 4 and LTE 4 (cysteinyl‐leukotrienes) levels occurred 4 h after ischaemia induction in the ipsilateral cortices of ischaemic compared to sham‐operated animals (3998±475 and 897±170 fmol g −1 tissue, respectively, P <0.01). The NMDA receptor antagonist MK‐801 and the adenosine A 2A receptor antagonist SCH 58261 were administered in vivo at doses known to reduce infarct size and compared with the leukotriene biosynthesis inhibitor MK‐886. 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, respectively) 4 h after permanent occlusion of the middle cerebral artery, whereas SCH 58261 (0.01 mg kg −1 i.v.) had no significant effects. MK‐886 (2 mg kg −1 i.v.) was also able to significantly reduce the cortical infarct size by 30% ( P <0.05). We conclude that cysteinyl‐leukotriene formation is associated with NMDA receptor activation, and that it represents a neurotoxic event, the inhibition of which is able to reduce brain infarct area in a focal ischaemic event.British Journal of Pharmacology (2001) 133 , 1323–1329; doi: 10.1038/sj.bjp.0704189