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 damage 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 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). 3. 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. 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, 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. 5. MK-886 (2 mg kg(-1) i.v.) was also able to significantly reduce the cortical 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 inhibition of which is able to reduce brain infarct area in a focal ischaemic event.
Ciceri
P
P
Laboratory of Molecular Pharmacology, Department of Pharmacological Sciences, University of Milan, Italy.
Rabuffetti
M
M
Monopoli
A
A
Nicosia
S
S
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003545:Cysteine / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D002722:Chlorobenzenes
D003545:Cysteine; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D018696:Neuroprotective Agents; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D018047:Receptors, Purinergic P1; D014230:Triazoles; C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; C112381:cysteinyl-leukotriene; C060893:MK-886; D002722:Chlorobenzenes