Löscher W, Jäckel R, Müller F
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, F.R.G.
Eur J Pharmacol. 1989 Apr 12;163(1):1-14. doi: 10.1016/0014-2999(89)90389-0.
The effects of three drugs, namely gamma-vinyl GABA (vigabatrin), gamma-acetylenic GABA, and aminooxyacetic acid, which increase brain GABA concentrations by irreversible inhibition of GABA degradation, were studied in amygdala-kindled rats. Vigabatrin 800 or 1,200 mg/kg i.p. 4 h after its administration, caused prolongation of behavioural seizures and electrographic afterdischarges recorded from the stimulated amygdala. One to three days after administration it dose dependently reduced seizure severity, seizure duration and afterdischarge duration in most animals. Determination of GABA levels in synaptosomes isolated from 12 brain regions of kindled rats 4 or 48 h after injection of 1,200 mg/kg vigabatrin indicated that the variable effects of this drug at different times after its administration could be related to differences in the time course of nerve terminal GABA increases in selective brain regions such as amygdala and corpus striatum. In contrast to vigabatrin, gamma-acetylenic GABA, 100 mg/kg i.p., reduced seizure severity in kindled rats as early as 4 h after its administration but afterdischarge duration increased significantly on subsequent days. Similar late increases in afterdischarge duration (and limbic seizure activity) after the time of maximum anticonvulsant effect had elapsed were also observed with vigabatrin, which could suggest that the anticonvulsant effect of such drugs is followed by withdrawal hyperexcitability. Aminooxyacetic acid, 20 mg/kg i.p., exerted no significant anticonvulsant effect in kindled rats but prolonged afterdischarge duration in several of the animals studied. The data suggest that GABA-T inhibitors, such as vigabatrin, differ from most antiepileptic drugs previously tested in the kindling model in that they may produce both anticonvulsant and proconvulsant effects at the same dose in the same animal as a function of time after administration.
研究了三种药物，即γ-乙烯基氨基丁酸（vigabatrin）、γ-乙炔基氨基丁酸和氨氧基乙酸对杏仁核点燃大鼠的影响，这三种药物通过不可逆抑制γ-氨基丁酸（GABA）降解来提高脑内GABA浓度。Vigabatrin腹腔注射800或1200mg/kg，给药4小时后，可使刺激杏仁核记录到的行为性癫痫发作和脑电图后放电时间延长。给药1至3天后，在大多数动物中它剂量依赖性地降低癫痫发作严重程度、发作持续时间和后放电持续时间。在注射1200mg/kg vigabatrin后4或48小时，对从点燃大鼠12个脑区分离的突触体中GABA水平的测定表明，该药物在给药后不同时间的不同作用可能与选择性脑区如杏仁核和纹状体中神经末梢GABA增加的时间进程差异有关。与vigabatrin不同，γ-乙炔基氨基丁酸腹腔注射100mg/kg，早在给药后4小时就降低了点燃大鼠的癫痫发作严重程度，但随后几天后放电持续时间显著增加。在vigabatrin最大抗惊厥作用消失后，也观察到类似的后放电持续时间（和边缘性癫痫发作活动）后期增加，这可能表明此类药物的抗惊厥作用之后会出现撤药后兴奋性过高。氨氧基乙酸腹腔注射20mg/kg，在点燃大鼠中未产生显著的抗惊厥作用，但在一些研究的动物中延长了后放电持续时间。数据表明，GABA转氨酶抑制剂，如vigabatrin，与先前在点燃模型中测试的大多数抗癫痫药物不同，因为它们在同一动物中同一剂量下可能根据给药后的时间产生抗惊厥和促惊厥两种作用。
