Wlaź P, Roliński Z, Czuczwar S J
Department of Pharmacology, Faculty of Veterinary Medicine, Agricultural University, Lublin, Poland.
Epilepsia. 1996 Jul;37(7):610-7. doi: 10.1111/j.1528-1157.1996.tb00624.x.
D-Cycloserine (DCS) is a high-efficacy partial agonist at the strychnine-insensitive glycine modulatory site within the N-methyl-D-aspartate (NMDA)-receptor/ionophore complex. Previous studies demonstrated that DCS exhibits anticonvulsant activity in a variety of experimental epilepsy models. In this study, we determined the influence of DCS in subprotective doses on the anticonvulsant action of phenytoin (PHT) and carbamazepine (CBZ) in mice.
Two electroconvulsive tests were used, i.e., determination of seizure threshold and maximal electroshock seizures. Antiepileptic drug-induced motor and long-term memory deficits were quantified by using the chimney test and the passive-avoidance test, respectively. In addition, plasma levels of PHT and CBZ were measured by fluorescence polarization immunoassay to exclude any pharmacokinetic interactions.
DCS, when used alone in doses of 80 and 160 mg/kg, significantly increased the threshold for electroconvulsive seizures. DCS in a wide range of doses (1.25-40 mg/kg) was combined with either PHT or CBZ and tested in electroconvulsive tests. DCS, at doses of 2.5 and 10 mg/kg, was the most effective in potentiating the threshold-increasing action of PHT; higher doses of DCS (20 and 40 mg/kg) were required to achieve a similar effect of CBZ. In maximal electroshock-induced seizures, DCS (10 mg/kg) augmented the protective action of PHT, but was ineffective at a dose of 40 mg/kg with CBZ. DCS did not potentiate the neurotoxicity produced by PHT and CBZ in the chimney test. Both PHT and CBZ induced impairments of long-term memory; PHT-induced memory adverse effects were counteracted by DCS (10 mg/kg). There was no such effect on CBZ-induced memory impairment, and a worsening influence was observed. Any pharmacokinetic interactions were excluded by measuring total and free plasma levels of both antiepileptic drugs.
Our results suggest that combining DCS with PHT and CBZ may be beneficial in treating epileptic seizures.
D-环丝氨酸（DCS）是N-甲基-D-天冬氨酸（NMDA）受体/离子通道复合物中对士的宁不敏感的甘氨酸调节位点的高效部分激动剂。先前的研究表明，DCS在多种实验性癫痫模型中表现出抗惊厥活性。在本研究中，我们确定了亚保护剂量的DCS对苯妥英（PHT）和卡马西平（CBZ）在小鼠体内抗惊厥作用的影响。
采用两种电惊厥试验，即癫痫阈值测定和最大电休克惊厥试验。分别使用烟囱试验和被动回避试验对抗癫痫药物引起的运动和长期记忆缺陷进行量化。此外，通过荧光偏振免疫测定法测量PHT和CBZ的血浆水平，以排除任何药代动力学相互作用。
单独使用80和160mg/kg剂量的DCS时，可显著提高电惊厥发作的阈值。将不同剂量（1.25 - 40mg/kg）的DCS与PHT或CBZ联合使用，并进行电惊厥试验。2.5和10mg/kg剂量的DCS在增强PHT提高阈值的作用方面最为有效；需要更高剂量的DCS（20和40mg/kg）才能对CBZ产生类似的效果。在最大电休克诱导的惊厥中，DCS（10mg/kg）增强了PHT的保护作用，但在40mg/kg剂量时对CBZ无效。在烟囱试验中，DCS未增强PHT和CBZ产生的神经毒性。PHT和CBZ均会导致长期记忆受损；DCS（10mg/kg）可抵消PHT引起的记忆不良反应。对CBZ引起的记忆损害没有这种作用，反而观察到有恶化影响。通过测量两种抗癫痫药物的总血浆水平和游离血浆水平，排除了任何药代动力学相互作用。
我们的结果表明，将DCS与PHT和CBZ联合使用可能对治疗癫痫发作有益。
