Sciotti V M, Roche F M, Grabb M C, Van Wylen D G
Department of Physiology, School of Medicine and Biomedical Sciences, State University of New York, Buffalo 14215.
J Cereb Blood Flow Metab. 1992 Jul;12(4):646-55. doi: 10.1038/jcbfm.1992.89.
The excitotoxic hypothesis suggests that cerebral ischemic damage results in part from the accumulation of the excitatory and potentially toxic neurotransmitters glutamate and aspartate. Adenosine, which also increases during cerebral ischemia, is proposed to inhibit neurotransmitter release. The purpose of this study was to determine if adenosine receptor blockade exacerbates the accumulation of glutamate and aspartate during cerebral ischemia. Microdialysis probes, implanted bilaterally in the caudate nucleus of halothane-anesthetized rats, were used to (1) assess changes in interstitial fluid (ISF) glutamate, aspartate, adenosine, and adenosine metabolites; (2) measure local cerebral blood flow (H2 clearance); and (3) deliver 8-(p-sulfophenyl)theophylline (SPT), an adenosine receptor antagonist, locally to the brain. The probe on one side of the brain was perfused with artificial cerebrospinal fluid (CSF) containing 10(-3) M SPT, while the probe on the opposite side received only artificial CSF. Animals were exposed to 20 min of ischemia (carotid occlusion+arterial blood pressure = 50 mm Hg) followed by 60 min of reperfusion. Dialysate glutamate and aspartate increased during and after cerebral ischemia, but were increased to a greater extent in the presence of adenosine receptor blockade. Likewise, the increase in dialysate adenosine and adenosine metabolites was enhanced on the side of locally administered SPT. These data suggest that endogenous adenosine attenuates the accumulation of glutamate and aspartate during cerebral ischemia.
兴奋性毒性假说认为，脑缺血损伤部分是由兴奋性且具有潜在毒性的神经递质谷氨酸和天冬氨酸的蓄积所致。在脑缺血期间也会增加的腺苷，被认为可抑制神经递质释放。本研究的目的是确定腺苷受体阻断是否会加剧脑缺血期间谷氨酸和天冬氨酸的蓄积。在氟烷麻醉大鼠的双侧尾状核植入微透析探针，用于：（1）评估细胞外液（ISF）中谷氨酸、天冬氨酸、腺苷及腺苷代谢产物的变化；（2）测量局部脑血流量（H2清除率）；（3）将腺苷受体拮抗剂8-（对-磺基苯基）茶碱（SPT）局部注入脑内。一侧脑的探针用含10（-3）M SPT的人工脑脊液（CSF）灌注，而另一侧的探针仅接受人工脑脊液。动物经历20分钟的缺血（颈动脉闭塞+动脉血压=50 mmHg），随后再灌注60分钟。脑缺血期间及之后，透析液中的谷氨酸和天冬氨酸增加，但在存在腺苷受体阻断的情况下增加幅度更大。同样，在局部给予SPT一侧，透析液中腺苷及腺苷代谢产物的增加更为明显。这些数据表明，内源性腺苷可减轻脑缺血期间谷氨酸和天冬氨酸的蓄积。
