Goda H, Ooboshi H, Nakane H, Ibayashi S, Sadoshima S, Fujishima M
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Eur J Pharmacol. 1998 Sep 18;357(2-3):149-55. doi: 10.1016/s0014-2999(98)00559-7.
Adenosine has been reported to have beneficial effects against ischemic brain damage, although the mechanisms are not fully clarified. To examine the role of adenosine on the ischemia-evoked release of neurotransmitters, we applied a highly selective agonist for adenosine A1 receptor, 2-chloro-N6-cyclopentyladenosine (CCPA), into the ischemic brain using in vivo brain dialysis, which directly delivered the agonist to the local brain area. Concentrations of extracellular amino acids (glutamate, aspartate, gamma-aminobutyric acid (GABA) and taurine) and regional blood flow in the striatum of spontaneously hypertensive rats (SHRs) were monitored during cerebral ischemia elicited by bilateral carotid artery occlusion for 40 min and recirculation. Striatal blood flow and basal levels of amino acids were not affected by direct perfusion of CCPA (10 microM or 100 microM). During ischemia, concentrations of glutamate, aspartate, GABA and taurine increased up to 37-, 30-, 96- and 31-fold, respectively, when vehicle alone was administered. Administration of CCPA did not affect the changes in regional blood flow during ischemia and reperfusion. Perfusion of CCPA (100 microM), however, significantly attenuated the ischemia-evoked release of aspartate (by 70%) and glutamate (by 73%). The ischemia-induced increase of GABA tended to be decreased by CCPA, although it was not statistically significant. In contrast, both low and high concentrations of CCPA had little effect on the release of taurine during ischemia. These results suggest that stimulation of adenosine A1 receptors selectively attenuated the ischemia-evoked release of excitatory amino acids, but not of inhibitory amino acids without affecting blood flow. This modulation of the release of amino acids by adenosine A1 receptor agonists may play a protective role against ischemic neuronal damage.
据报道，腺苷对缺血性脑损伤具有有益作用，但其机制尚未完全阐明。为了研究腺苷对缺血诱发的神经递质释放的作用，我们使用体内脑透析技术，将一种高度选择性的腺苷A1受体激动剂2-氯-N6-环戊基腺苷（CCPA）应用于缺血脑，该技术可将激动剂直接输送到局部脑区。在双侧颈动脉闭塞40分钟并再灌注引起的脑缺血期间，监测自发性高血压大鼠（SHR）纹状体中细胞外氨基酸（谷氨酸、天冬氨酸、γ-氨基丁酸（GABA）和牛磺酸）的浓度以及局部血流量。直接灌注CCPA（10微摩尔或100微摩尔）对纹状体血流量和氨基酸的基础水平没有影响。在缺血期间，单独给予载体时，谷氨酸、天冬氨酸、GABA和牛磺酸的浓度分别增加了37倍、30倍、96倍和31倍。给予CCPA并不影响缺血和再灌注期间局部血流量的变化。然而，灌注CCPA（100微摩尔）可显著减轻缺血诱发的天冬氨酸释放（降低70%）和谷氨酸释放（降低73%）。CCPA倾向于降低缺血诱导的GABA增加，尽管差异无统计学意义。相比之下，低浓度和高浓度的CCPA对缺血期间牛磺酸的释放几乎没有影响。这些结果表明，刺激腺苷A1受体可选择性减轻缺血诱发的兴奋性氨基酸释放，但不影响抑制性氨基酸释放，且不影响血流量。腺苷A1受体激动剂对氨基酸释放的这种调节作用可能对缺血性神经元损伤起到保护作用。
