Zheng Thomas, Clarke Alison L, Morris Margaret J, Reid Christopher A, Petrou Steven, O'Brien Terence J
Department of Medicine The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia.
Epilepsia. 2009 Jan;50(1):83-7. doi: 10.1111/j.1528-1167.2008.01759.x. Epub 2008 Aug 19.
Studies in genetic absence epileptic rats from Strasbourg (GAERS) indicate that enhancement of gamma aminobutyric acid (GABA(A)) receptor activity is a critical mechanism in the aggravation of seizures by carbamazepine (CBZ). We examined whether structural analogs of CBZ, oxcarbazepine (OXC), and its active metabolite, monohydroxy derivative (MHD), also potentiate GABA(A) receptor current and aggravate seizures.
In vitro studies in Xenopus oocytes compared the three drugs' effect on GABA(A) receptor currents. In vivo studies compared seizure activity in GAERS after intraperitoneal drug administration.
OXC potentiated GABA(A) receptor current and aggravated seizures in GAERS, similarly to the effect of CBZ. Conversely, MHD showed only a minor potentiation of GABA(A) receptor current and did not aggravate seizures.
A hydroxyl group at the C-10 position on the CBZ tricyclic structure in MHD reduces GABA(A) receptor potentiation and seizure aggravation. Reports of the aggravation of absence seizures in patients taking OXC may result from circulating unmetabolized OXC rather than MHD.
对来自斯特拉斯堡的遗传性失神癫痫大鼠（GAERS）的研究表明，增强γ-氨基丁酸（GABA(A)）受体活性是卡马西平（CBZ）加重癫痫发作的关键机制。我们研究了CBZ的结构类似物奥卡西平（OXC）及其活性代谢物单羟基衍生物（MHD）是否也能增强GABA(A)受体电流并加重癫痫发作。
在非洲爪蟾卵母细胞中进行的体外研究比较了这三种药物对GABA(A)受体电流的影响。体内研究比较了腹腔注射药物后GAERS的癫痫发作活动。
与CBZ的作用相似，OXC增强了GAERS的GABA(A)受体电流并加重了癫痫发作。相反，MHD仅对GABA(A)受体电流有轻微增强作用，且未加重癫痫发作。
MHD中CBZ三环结构C-10位上的羟基降低了GABA(A)受体的增强作用和癫痫发作的加重。服用OXC的患者失神发作加重的报道可能是由于未代谢的OXC循环所致，而非MHD。
