Prostaglandin-mediated control of rat brain kynurenic acid synthesis--opposite actions by COX-1 and COX-2 isoforms.
Kynurenic acid (KYNA), an endogenous glutamate-receptor antagonist preferentially blocking NMDA-receptors, has analgesic properties and has also been implicated in the pathophysiology of schizophrenia. Recently, the non-steroid anti-inflammatory drug (NSAID) diclofenac was found to increase rat brain KYNA. Here, we analyze whether cyclooxygenase (COX)-1 or COX-2 modulate the levels of rat brain KYNA. The non-selective COX-inhibitor diclofenac (50 mg/kg, i.p.) or indomethacin (50 mg/kg, i.p.), a non-selective inhibitor with a preferential selectivity for COX-1, produced an elevation in brain KYNA. In contrast, the COX-2 selective inhibitors parecoxib (25 mg/kg, i.p.) or meloxicam (5 mg/kg, i.p.) decreased brain KYNA. Both elevation and lowering of brain KYNA by indomethacin or parecoxib, respectively, were prevented by the prostaglandin E1/E2 agonist misoprostol (1 mg/kg, s.c.). It is proposed that increased brain KYNA formation induced by NSAIDs displaying an inhibitory action on COX-1 contribute to their analgesic efficacy as well as to their psychiatric side effects.
Schwieler
L
L
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Lilly.Schwieler@fyfa.ki.se
Erhardt
S
S
Erhardt
C
C
Engberg
G
G
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004008:Diclofenac / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D000077239:Meloxicam; D011453:Prostaglandins / Q000378:metabolism*; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007555:Isoxazoles; D011453:Prostaglandins; D020033:Protein Isoforms; D013843:Thiazines; D013844:Thiazoles; D004008:Diclofenac; C409945:parecoxib; D007736:Kynurenic Acid; D000077239:Meloxicam; D007213:Indomethacin