Doi Taku, Ueda Yuto, Tokumaru Jun, Willmore L James
Department of Psychiatry, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Brain Res Mol Brain Res. 2005 Dec 14;142(2):91-6. doi: 10.1016/j.molbrainres.2005.09.010. Epub 2005 Nov 7.
To assess the molecular effects of the antiepileptic drug clobazam (CLB, 1,5-benzodiazepine), a benzodiazepine effective in the management of epilepsy, we performed a series of experiments using rats with chronic, spontaneous recurrent seizures induced by amygdalar injection of FeCl(3). Experimental animals were treated for 14 days with CLB. We then measured the expression of glutamate and GABA transporter proteins and evaluated the changes that occurred in these proteins using both experimental and control animals. CLB treatment was associated with an increase in the production of GLT-1 in the contra-lateral hippocampus of animals receiving amygdalar FeCl(3) and CLB treatment. CLB treatment up-regulated the GABA transporter GAT3 in the contra-lateral hippocampus of animals with chronic, recurrent seizures. In contrast, CLB had no effect on the expression of EAAC1 and GAT1 in the hippocampus or the cortex in control animal groups. Chronic epileptogenesis may be associated with down-regulation of the production of glial excitatory amino acid transporters, GLAST and GLT-1, proteins that cause increase in the basal extracellular concentrations of glutamate. Elevated GABA transporter expression results in increased reverse transport of GABA to the extracellular space during periods of excitation. In addition to allosteric activation of GABA(A) receptors, this study suggests that CLB might exhibit its antiepileptic action by increasing GLT-1 expression and GAT3 in the hippocampus of rats with chronic seizures.
为评估抗癫痫药物氯巴占（CLB，1,5-苯二氮䓬）的分子效应，氯巴占是一种对癫痫治疗有效的苯二氮䓬类药物，我们使用经杏仁核注射FeCl₃诱导产生慢性自发性复发性癫痫的大鼠进行了一系列实验。实验动物用氯巴占治疗14天。然后我们测量了谷氨酸和GABA转运蛋白的表达，并使用实验动物和对照动物评估了这些蛋白发生的变化。氯巴占治疗与接受杏仁核FeCl₃和氯巴占治疗的动物对侧海马中GLT-1的产生增加有关。氯巴占治疗使患有慢性复发性癫痫的动物对侧海马中的GABA转运体GAT3上调。相比之下，氯巴占对对照动物组海马或皮质中EAAC1和GAT1的表达没有影响。慢性癫痫发生可能与胶质细胞兴奋性氨基酸转运体GLAST和GLT-1产生的下调有关，这些蛋白会导致谷氨酸基础细胞外浓度增加。GABA转运体表达升高导致在兴奋期GABA反向转运到细胞外空间增加。除了对GABA(A)受体的变构激活外，本研究表明氯巴占可能通过增加慢性癫痫大鼠海马中GLT-1的表达和GAT3来发挥其抗癫痫作用。
