Chesi A J, Stone T W
Division of Neuroscience and Biomedical Systems, University of Glasgow, Scotland, UK.
Exp Brain Res. 1997 Feb;113(2):303-10. doi: 10.1007/BF02450328.
Despite its potent proconvulsant effects in vitro, the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) does not induce seizures when administered in vivo. This contrasts with the effects of less selective adenosine antagonists such as theophylline or cyclopentlytheophylline, and led us to reexamine the nature of DPCPX-induced epileptiform activity. In the present study, we report that proconvulsant effects of bath-applied DPCPX in rat hippocampal slices are only observed after a preceding stimulus such as NMDA receptor activation or brief tetanic stimulation. While this may be due to the absence of a basal "purinergic tone", the relatively high interstitial concentrations of adenosine present in the slice suggest that access of the drug to A1 receptors may instead be prevented by tightly coupled endogenous adenosine, with the ternary adenosine-A1 receptor-G protein complex stabilised in the high-affinity conformation by a coupling cofactor. This implies that a substantial percentage of adenosine A1 receptors are inactive under physiological conditions, but that access of adenosine A1 receptor antagonists may be facilitated under pathological conditions. Once induced, DPCPX-evoked spiking persists for long periods of time. A "kindling" effect of A1 receptor blockade is unlikely, since persistent spiking is not usually observed with less selective A1 antagonists even after prolonged application. Alternatively, endogenous adenosine released during increased neuronal activity may activate A2 receptors during selective A1 blockade. The most important factor determining the duration of DPCPX-induced spiking, however, may be a persistence of the drug in the tissue and subsequent access to the A1 receptor via a membrane-delineated pathway, since DPCPX-induced spiking could be shown to decrease markedly after a transient superfusion of theophylline. This hypothesis, which implies that the apparent affinity of adenosine antagonists for the A1 receptor is in part a function of their membrane partitioning coefficient, is supported by a close correlation between alkylxanthine logP values obtained from the literature and their Ki value at A1 receptors, but not at the enzyme phosphodiesterase, whose xanthine binding site is presented to the cytosol. The implications for the therapeutic value of purinergic drugs are discussed.
尽管腺苷A1受体拮抗剂1,3 - 二丙基 - 8 - 环戊基黄嘌呤（DPCPX）在体外具有强大的促惊厥作用，但在体内给药时并不会诱发癫痫发作。这与选择性较低的腺苷拮抗剂如茶碱或环戊烯基茶碱的作用形成对比，促使我们重新审视DPCPX诱导的癫痫样活动的本质。在本研究中，我们报告称，仅在先前的刺激（如NMDA受体激活或短暂强直刺激）之后，才会观察到浴加DPCPX在大鼠海马切片中产生的促惊厥作用。虽然这可能是由于缺乏基础的“嘌呤能张力”，但切片中相对较高的腺苷间质浓度表明，药物可能因紧密偶联的内源性腺苷而无法接近A1受体，三元腺苷 - A1受体 - G蛋白复合物通过偶联辅因子稳定在高亲和力构象中。这意味着在生理条件下，相当一部分腺苷A1受体是无活性的，但在病理条件下，腺苷A1受体拮抗剂的作用可能会增强。一旦诱发，DPCPX诱发的尖峰活动会持续很长时间。A1受体阻断不太可能产生“点燃”效应，因为即使在长时间应用后，选择性较低的A1拮抗剂通常也不会观察到持续的尖峰活动。另外，在选择性A1阻断期间，神经元活动增加时释放的内源性腺苷可能会激活A2受体。然而，决定DPCPX诱导的尖峰活动持续时间的最重要因素可能是药物在组织中的持续存在以及随后通过膜界定途径接近A1受体，因为在短暂灌注茶碱后，DPCPX诱导的尖峰活动会明显减少。这一假设意味着腺苷拮抗剂对A1受体的表观亲和力部分取决于其膜分配系数，从文献中获得的烷基黄嘌呤logP值与其在A1受体处的Ki值密切相关，但与磷酸二酯酶处的情况无关，磷酸二酯酶的黄嘌呤结合位点面向细胞质。文中讨论了嘌呤能药物治疗价值的相关影响。
