Kertész Szabolcs, Kapus Gábor, Lévay György
EGIS Pharmaceuticals Ltd., Division of Preclinical Research, CNS Pharmacology, H-1475 Budapest 10, P.O. Box 100, Hungary.
Brain Res. 2004 Oct 29;1025(1-2):123-9. doi: 10.1016/j.brainres.2004.08.010.
The functional role of AMPA and kainate receptors in spreading depression (SD) was investigated in the isolated chicken retina. Competitive (NBQX) and non-competitive (GYKI 52466, GYKI 53405 and GYKI 53655) antagonists of the AMPA receptor inhibited AMPA-induced SD in a concentration-dependent manner. Concentrations of drugs caused 50% inhibition (IC(50) values) are 0.2, 16.6, 7.0 and 1.4 microM, respectively. AMPA receptor positive modulator cyclothiazide was more effective in the potentiation of SD evoked by AMPA than by kainate. Slight potentiation of either AMPA- or kainate-induced SD was observed only at high concentration (1 mg/ml) by the kainate receptor modulator concanavalin A. Compounds that positively modulate AMPA receptor function (cyclothiazide, IDRA-21, S 18986, 1-BCP and aniracetam) caused a concentration-dependent potentiation in SD. Concentrations of drugs that caused 50% potentiation (estimated EC(50) values) are 9, 135, 142, 450 and 1383 microM, respectively. Interaction between cyclothiazide, aniracetam or S 18986 administered with each other, or with GYKI 52466, respectively, was also investigated. When cyclothiazide and S 18986 were co-applied, their effects seemed to be additive. However, lack of additivity was obtained when S 18986 was added together with aniracetam. Positive modulators applied at equiactive concentrations reduced the inhibitory action of GYKI 52466 and differently shifted its concentration-response curve. In this respect, S 18986 was the most effective (IC(50) of GYKI 52466 changed from 16.6 to 51.9 microM). Our findings indicate the contribution of AMPA rather than kainate receptors in the mediation of retinal spreading depression. Our data further support the idea that multiple positive modulatory sites are present on the AMPA receptor complex in addition to a negative modulatory site.
在离体鸡视网膜中研究了AMPA和海人酸受体在扩散性抑制（SD）中的功能作用。AMPA受体的竞争性拮抗剂（NBQX）和非竞争性拮抗剂（GYKI 52466、GYKI 53405和GYKI 53655）以浓度依赖性方式抑制AMPA诱导的SD。引起50%抑制的药物浓度（IC50值）分别为0.2、16.6、7.0和1.4微摩尔。AMPA受体正向调节剂环噻嗪对AMPA诱发的SD的增强作用比对海人酸诱发的SD更有效。仅在高浓度（1毫克/毫升）时，海人酸受体调节剂伴刀豆球蛋白A才观察到对AMPA或海人酸诱导的SD有轻微增强作用。正向调节AMPA受体功能的化合物（环噻嗪、IDRA-21、S 18986、1-BCP和阿尼西坦）在SD中引起浓度依赖性增强。引起50%增强的药物浓度（估计的EC50值）分别为9、135、142、450和1383微摩尔。还分别研究了环噻嗪、阿尼西坦或S 18986相互之间或与GYKI 52466一起给药时的相互作用。当环噻嗪和S 18986联合应用时，它们的作用似乎是相加的。然而，当S 18986与阿尼西坦一起添加时，未获得相加性。以等效活性浓度应用的正向调节剂降低了GYKI 52466的抑制作用，并不同程度地移动了其浓度-反应曲线。在这方面，S 18986最有效（GYKI 52466的IC50从16.6微摩尔变为51.9微摩尔）。我们的研究结果表明，在视网膜扩散性抑制的介导中，AMPA受体而非海人酸受体起作用。我们的数据进一步支持了这样一种观点，即除了一个负向调节位点外，AMPA受体复合物上还存在多个正向调节位点。
