Di Iorio P, Battaglia G, Ciccarelli R, Ballerini P, Giuliani P, Poli A, Nicoletti F, Caciagli F
Institute of Pharmacology, University of Chieti and Catania, Catania, Italy.
J Neurochem. 1996 Jul;67(1):302-9. doi: 10.1046/j.1471-4159.1996.67010302.x.
Electrical stimulation of rat hippocampal slices evoked the release of excitatory amino acids and purines, as reflected by a time-dependent increase in the extracellular levels of glutamate and adenosine, as well as by the increased efflux of radioactivity in slices preloaded with both [14C]glutamate and [3H]adenosine. The evoked release of excitatory amino acids and purines was amplified when slices were exposed to 8-cyclopentyl-1,3-dipropylxanthine (a selective A1 adenosine receptor antagonist), (+)-alpha-methyl-4-carboxyphenylglycine [a mixed antagonist of metabotropic glutamate receptors (mGluRs)], or (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine (a selective antagonist of class II mGluRs). In contrast, 2-chloro-N6-cyclopentyladenosine (CCPA; a selective A1 receptor agonist) or (2S,1R,2R,3R)-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; a selective agonist of class II mGluRs) reduced the evoked release of excitatory amino acids and purines. CCPA and DCG-IV also reduced the increase in cyclic AMP formation induced by either forskolin or electrical stimulation in hippocampal slices. The inhibitory effect of CCPA and DCG-IV on release or cyclic AMP formation was less than additive. We conclude that the evoked release of excitatory amino acids and purines is under an inhibitory control by A1 receptors and class II mGluRs, i.e., mGluR2 or 3, which appear to operate through a common transduction pathway. In addition, although these receptors are activated by endogenous adenosine and glutamate, they can still respond to pharmacological agonists. This provides a rationale for the use of A1 or class II mGluR agonists as neuroprotective agents in experimental models of excitotoxic neuronal degeneration.
对大鼠海马切片进行电刺激可诱发兴奋性氨基酸和嘌呤的释放，这表现为细胞外谷氨酸和腺苷水平随时间增加，以及预先加载了[14C]谷氨酸和[3H]腺苷的切片中放射性外流增加。当切片暴露于8-环戊基-1,3-二丙基黄嘌呤（一种选择性A1腺苷受体拮抗剂）、(+)-α-甲基-4-羧基苯基甘氨酸[一种代谢型谷氨酸受体（mGluRs）的混合拮抗剂]或(2S,3S,4S)-2-甲基-2-(羧基环丙基)甘氨酸（一种II类mGluRs的选择性拮抗剂）时，兴奋性氨基酸和嘌呤的诱发释放会增强。相反，2-氯-N6-环戊基腺苷（CCPA；一种选择性A1受体激动剂）或(2S,1R,2R,3R)-(2,3-二羧基环丙基)甘氨酸（DCG-IV；一种II类mGluRs的选择性激动剂）可减少兴奋性氨基酸和嘌呤的诱发释放。CCPA和DCG-IV还可减少由福斯高林或海马切片电刺激诱导的环磷酸腺苷形成的增加。CCPA和DCG-IV对释放或环磷酸腺苷形成的抑制作用小于相加效应。我们得出结论，兴奋性氨基酸和嘌呤的诱发释放受A1受体和II类mGluRs（即mGluR2或3）的抑制性控制，它们似乎通过共同的转导途径发挥作用。此外，尽管这些受体被内源性腺苷和谷氨酸激活，但它们仍可对药理激动剂作出反应。这为在兴奋性毒性神经元变性的实验模型中使用A1或II类mGluR激动剂作为神经保护剂提供了理论依据。
