Enhancement of brain kynurenic acid production by anticonvulsants--novel mechanism of antiepileptic activity?
In this study, we describe the effect of antiepileptic drugs on the production of kynurenic acid in rat cortical slices, and on the activity of kynurenic acid biosynthetic enzymes, kynurenine aminotransferases (KATs I and II) in the brain tissue. Phenobarbital, felbamate, phenytoin and lamotrigine (all at 0.5-3.0 mM) enhanced kynurenic acid production in vitro, and stimulated the activity of KAT I. In contrast, vigabatrin, gabapentin and tiagabine inhibited kynurenic acid synthesis in cortical slices with IC(50) of 3.9 (2.8-7.9), 3.7 (2.5-5.4) and 7.5 (3.5-14.3) mM, respectively. Vigabatrin, gabapentin and tiagabine reduced also the activity of KAT I with IC(50) of 1.6 (1.1-2.4), 0.1 (0.01-0.15), 0.9 (0.7-1.2) mM, and the activity of KAT II with IC(50) values of 6.0 (4.8-7.5), 0.2 (0.1-0.3) and 2.0 (1.5-2.6) mM, respectively. In conclusion, the enhancement of kynurenic acid formation displayed by carbamazepine, phenytoin, phenobarbital, felbamate and lamotrigine seems to be a novel mechanism, synergistic with other actions of these drugs, and potentially valuable in terms of better control of epilepsy.
Kocki
Tomasz
T
Department of Pharmacology, Skubiszewski Medical University, Lublin, Poland.
Wielosz
Marian
M
Turski
Waldemar A
WA
Urbanska
Ewa M
EM
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D000637:Transaminases / Q000378:metabolism
D000927:Anticonvulsants; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D007736:Kynurenic Acid