Liu Lige, Zheng Thomas, Morris Margaret J, Wallengren Charlott, Clarke Alison L, Reid Christopher A, Petrou Steven, O'Brien Terence J
Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Royal Parade, Parkville 3050, Victoria, Australia.
J Pharmacol Exp Ther. 2006 Nov;319(2):790-8. doi: 10.1124/jpet.106.104968. Epub 2006 Aug 8.
Carbamazepine (CBZ) aggravates many generalized seizures types, particularly absence seizures, but the mechanisms underlying this are poorly understood. GABA signaling within the reticular nucleus (Rt) and the ventrobasal complex (VB) of the thalamus is critical to the neurophysiology of absence seizures. The hypothesis that CBZ aggravates absence seizures by acting at the VB thalamus via a GABA(A) receptor-mediated mechanism was investigated in a genetic rat model, generalized absence epilepsy rats from Strasbourg (GAERS). Seizure activity was quantified by a 90-min electroencephalogram recording postdrug injection. Intracerebroventricular injections of CBZ (15 microg in 4 microl) resulted in seizure aggravation versus vehicle treatment, with a mean increase in seizure time of 40%. This indicates that CBZ acts directly, rather than via a metabolite, on the brain to aggravate seizures. Seizure aggravation also occurred following bilateral microinjection of CBZ (0.75 microg in 0.2 microl) into the VB (53%) but not following injection into the Rt (-9%). However, seizure aggravation was blocked when the GABA(A) receptor antagonist, bicuculline (BIC, 0.04 microg in 0.2 microl), was coinjected with CBZ into the VB. Injection of BIC alone (versus vehicle) into the VB also blocked seizure aggravation following systemic administration of CBZ (15 mg/kg i.p.). In vitro studies in Xenopus oocytes expressing recombinant GABA(A) receptors demonstrated that CBZ produced a dose-dependent potentiation of the GABA current at a physiological relevant concentration range (1-100 microM). These data demonstrate that CBZ acts at the VB thalamus to aggravate absence seizures in GAERS and that activation of GABA(A) receptors is critical to this effect.
卡马西平（CBZ）会加重多种全身性癫痫发作类型，尤其是失神发作，但其潜在机制尚不清楚。丘脑网状核（Rt）和腹侧基底复合体（VB）内的GABA信号传导对失神发作的神经生理学至关重要。在一种遗传性大鼠模型——来自斯特拉斯堡的全身性失神癫痫大鼠（GAERS）中，研究了CBZ通过GABA(A)受体介导的机制作用于丘脑VB从而加重失神发作的假说。通过给药后90分钟的脑电图记录对癫痫发作活动进行量化。脑室内注射CBZ（4微升中含15微克）与注射赋形剂相比会导致癫痫发作加重，癫痫发作时间平均增加40%。这表明CBZ直接作用于大脑而非通过代谢产物来加重癫痫发作。双侧向VB微量注射CBZ（0.2微升中含0.75微克）后也出现癫痫发作加重（53%），但向Rt注射后未出现（-9%）。然而，当GABA(A)受体拮抗剂荷包牡丹碱（BIC，0.2微升中含0.04微克）与CBZ共同注射到VB时，癫痫发作加重被阻断。单独向VB注射BIC（与赋形剂相比）也能阻断全身给予CBZ（15毫克/千克腹腔注射）后的癫痫发作加重。在表达重组GABA(A)受体的非洲爪蟾卵母细胞中的体外研究表明，在生理相关浓度范围（1 - 100微摩尔）内，CBZ对GABA电流产生剂量依赖性增强作用。这些数据表明，CBZ作用于丘脑VB以加重GAERS中的失神发作，且GABA(A)受体的激活对这种作用至关重要。
