Waldmeier P C, Martin P, Stöcklin K, Portet C, Schmutz M
Research Department, Ciba-Geigy Ltd., Basel, Switzerland.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Jul;354(2):164-72. doi: 10.1007/BF00178716.
Lamotrigine, carbamazepine and oxcarbazepine inhibit veratrine-induced neurotransmitter release from rat brain slices in concentrations corresponding to those reached in plasma or brain in experimental animals or humans after anticonvulsant doses, presumably due to their sodium channel blocking properties. Microdialysis measurements of extracellular glutamate and aspartate were carried out in conscious rats in order to investigate whether corresponding effects occur in vivo Veratridine (10 microM) was applied via the perfusion medium to the cortex and the corpus striatum in the presence of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (1 mM in perfusion medium). Maximally effective anticonvulsant doses of carbamazepine (30 mg/kg), oxcarbazepine (60 mg/kg) and lamotrigine (15 mg/kg) were given orally. The uptake inhibitor increased extracellular glutamate and aspartate about 2-fold in striatum and about 7-fold and 3-fold, respectively, in cortex. Veratridine caused a further 2-3-fold increase in extracellular glutamate in striatum and cortex, respectively, but its effect on extracellular aspartate was less marked in both areas. None of the anticonvulsant compounds affected the veratridine-induced increases in extracellular glutamate or aspartate in the striatum which were, however, markedly inhibited by tetrodotoxin (1 microM) and thus are sensitive to sodium channel blockade. In the cortex the same drugs at the same doses did cause about 50% inhibition of the veratridine-induced increase in extracellular glutamate. Carbamazepine and to a lesser extent lamotrigine, but not oxcarbazepine, also inhibited the veratridine-induced increase in extracellular aspartate in the cortex. Although our results might seem to support the view that inhibition of glutamate and aspartate release is responsible for the anticonvulsant effects of lamotrigine, carbamazepine and oxcarbazepine, two complementary findings argue against this interpretation. First, as previously shown, inhibition of electrically induced released of glutamate requires 5 to 7 times higher concentrations of these compounds than release elicited by veratrine. Second, the present study indicates that doses totally suppressing convulsions caused no inhibition in the striatum and at best a 50% inhibition in the brain cortex. From this we conclude that the doses used here, although to some extent effective against veratridine, did not suppress the release of GLU and ASP elicited by the normal ongoing electrical activity of the glutamatergic and aspartatergic neurons and that the mechanism of the suppression of convulsions must be sought elsewhere.
拉莫三嗪、卡马西平和奥卡西平在浓度相当于实验动物或人类服用抗惊厥剂量后血浆或大脑中达到的浓度时，可抑制藜芦碱诱导的大鼠脑片神经递质释放，这可能归因于它们的钠通道阻断特性。为了研究体内是否会出现相应的作用，对清醒大鼠进行了细胞外谷氨酸和天冬氨酸的微透析测量。在谷氨酸摄取抑制剂L-反式-吡咯烷-2,4-二羧酸（灌注培养基中1 mM）存在的情况下，通过灌注培养基将藜芦碱（10 microM）应用于皮质和纹状体。口服给予卡马西平（30 mg/kg）、奥卡西平（60 mg/kg）和拉莫三嗪（15 mg/kg）的最大有效抗惊厥剂量。摄取抑制剂使纹状体中的细胞外谷氨酸和天冬氨酸分别增加约2倍，在皮质中分别增加约7倍和3倍。藜芦碱分别使纹状体和皮质中的细胞外谷氨酸进一步增加2 - 3倍，但其对细胞外天冬氨酸的作用在两个区域均不太明显。抗惊厥化合物均未影响藜芦碱诱导的纹状体中细胞外谷氨酸或天冬氨酸的增加，然而，这些增加被河豚毒素（1 microM）显著抑制，因此对钠通道阻断敏感。在皮质中，相同剂量的相同药物确实使藜芦碱诱导的细胞外谷氨酸增加受到约50%的抑制。卡马西平和程度较轻的拉莫三嗪，但不是奥卡西平，也抑制了皮质中藜芦碱诱导的细胞外天冬氨酸增加。尽管我们的结果似乎支持这样的观点，即抑制谷氨酸和天冬氨酸释放是拉莫三嗪、卡马西平和奥卡西平抗惊厥作用的原因，但有两个补充发现反对这种解释。首先，如先前所示，抑制电诱导的谷氨酸释放所需的这些化合物浓度比藜芦碱诱导的释放高5至7倍。其次，本研究表明，完全抑制惊厥的剂量在纹状体中没有抑制作用，在大脑皮质中最多只有50%的抑制作用。由此我们得出结论，这里使用的剂量虽然在一定程度上对藜芦碱有效，但并未抑制谷氨酸能和天冬氨酸能神经元正常持续电活动引起的谷氨酸和天冬氨酸释放，惊厥抑制机制必须在其他地方寻找。
