Kocki Tomasz, Wielosz Marian, Turski Waldemar A, Urbanska Ewa M
Department of Pharmacology, Skubiszewski Medical University, Lublin, Poland.
Eur J Pharmacol. 2006 Jul 17;541(3):147-51. doi: 10.1016/j.ejphar.2006.05.015.
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.
在本研究中，我们描述了抗癫痫药物对大鼠皮质切片中犬尿喹啉酸生成的影响，以及对脑组织中犬尿喹啉酸生物合成酶——犬尿氨酸转氨酶（KAT I和KAT II）活性的影响。苯巴比妥、非氨酯、苯妥英和拉莫三嗪（均为0.5 - 3.0 mM）在体外增强了犬尿喹啉酸的生成，并刺激了KAT I的活性。相比之下，氨己烯酸、加巴喷丁和噻加宾抑制了皮质切片中犬尿喹啉酸的合成，其半数抑制浓度（IC50）分别为3.9（2.8 - 7.9）、3.7（2.5 - 5.4）和7.5（3.5 - 14.3）mM。氨己烯酸、加巴喷丁和噻加宾还降低了KAT I的活性，其IC50分别为1.6（1.1 - 2.4）、0.1（0.01 - 0.15）、0.9（0.7 - 1.2）mM，以及KAT II的活性，其IC50值分别为6.0（4.8 - 7.5）、0.2（0.1 - 0.3）和2.0（1.5 - 2.6）mM。总之，卡马西平、苯妥英、苯巴比妥、非氨酯和拉莫三嗪所表现出的犬尿喹啉酸生成增强似乎是一种新机制，与这些药物的其他作用协同，并且在更好地控制癫痫方面可能具有潜在价值。
