Vrooman L, Jhamandas K, Boegman R J, Beninger R J
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ont., Canada.
Brain Res. 1993 Nov 12;627(2):193-8. doi: 10.1016/0006-8993(93)90320-m.
Since picolinic acid, a tryptophan metabolite yielded by the kynurenine pathway, selectively attenuates quinolinic and kainic acid excitotoxicity that is dependent on the presence of a glutamatergic afferent input, it was hypothesized that this agent may inhibit the presynaptic release of glutamate. Using superfused rat striatal slices, this study examined the potential of picolinic acid, and related pyridine monocarboxylic acids, to modify kainic acid-induced glutamate release. Kainic acid (0.25, 0.5 and 1.0 mM) stimulated the release of glutamate, an effect which was calcium dependent and was attenuated in the presence of the kainate/AMPA receptor antagonist, 6,7-dinitroquinoxalene-2,3-dione (500 microM). Picolinic acid significantly decreased glutamic acid release evoked by exposure of striatal slices to 1 mM kainate in the presence of calcium. The inhibitory action of picolinic acid on kainate-induced release was also shared by nicotinic and isonicotinic acid. In the absence of external calcium, kainic acid-induced glutamate release was significantly reduced by approximately 65%. Under this condition, picolinic acid (100 microM) failed to influence kainic acid-induced release. Picolinic acid (100 microM) itself increased glutamate release by 35% over basal release. While the ability of picolinic acid to inhibit excitotoxin-induced release supports the notion that it may act presynaptically to modify excitotoxicity, lack of structural specificity in its action tends to cast doubt on this mechanism of action.
由于犬尿氨酸途径产生的色氨酸代谢产物吡啶甲酸可选择性减轻喹啉酸和红藻氨酸的兴奋性毒性，这种兴奋性毒性依赖于谷氨酸能传入输入的存在，因此推测该药物可能抑制谷氨酸的突触前释放。本研究使用灌流的大鼠纹状体切片，检测了吡啶甲酸及相关吡啶单羧酸改变红藻氨酸诱导的谷氨酸释放的可能性。红藻氨酸（0.25、0.5和1.0 mM）刺激了谷氨酸的释放，这一效应依赖于钙，并且在红藻氨酸/AMPA受体拮抗剂6,7-二硝基喹喔啉-2,3-二酮（500 microM）存在时减弱。在有钙的情况下，吡啶甲酸显著降低了纹状体切片暴露于1 mM红藻氨酸时诱发的谷氨酸释放。烟酸和异烟酸也具有吡啶甲酸对红藻氨酸诱导释放的抑制作用。在无细胞外钙的情况下，红藻氨酸诱导的谷氨酸释放显著降低了约65%。在此条件下，吡啶甲酸（100 microM）未能影响红藻氨酸诱导的释放。吡啶甲酸（100 microM）本身使谷氨酸释放量比基础释放量增加了35%。虽然吡啶甲酸抑制兴奋性毒素诱导释放的能力支持了它可能通过突触前作用来改变兴奋性毒性的观点，但其作用缺乏结构特异性这一点往往让人对这种作用机制产生怀疑。
