Effects of adenosine agonists and an antagonist on excitatory transmitter release from the ischemic rabbit hippocampus

The purpose of this study was to determine the effects of adenosine agonist s and an antagonist on ischemia-induced extracellular glutamate concentrati ons in an animal model of transient cerebral ischemia using in vivo cerebra l microdialysis. Fifty New Zealand white rabbits were randomly assigned to one of five groups (normothermia, hypothermia, cyclopentyladenosine (CPA), theophylline, or propentofylline). Microdialysis probes were stereotactical ly placed in the dorsal hippocampus. Twenty minutes before the onset of isc hemia, either 1 mg/kg CPA, 5 mg/kg propentofylline, or 20 mg/kg theophyllin e were administered intravenously. Esophageal temperature was maintained at 38 degrees C, except in the hypothermic animals, which were cooled to 30 d egrees C throughout the entire experiment. Two 12-min periods of cerebral i schemia, separated by a 105-min interval of reperfusion, were produced by i nflating a neck tourniquet. High-performance liquid chromatography was used to determine the glutamate concentration in the microdialysate. There were no significant increases in glutamate concentrations during the first isch emic period in any of the five groups. During the second ischemic episode, glutamate concentrations in the normothermic group peaked at levels approxi mately three times higher than the initial values. A similar pattern of cha nges in glutamate concentrations was observed in the CPA, propentofylline, and theophylline groups. In the hypothermic group, the concentrations of gl utamate remained at baseline levels during the entire experiment. Contrary to expectations, neither the adenosine agonists (CPA, propentofylline) nor the antagonist (theophylline) had any effect on extracellular glutamate con centrations in the peri-ischemic period. Although adenosine and its analogs may be cerebroprotective agents, their mechanism of action is not fully un derstood. The data derived from this study indicates that the acute adminis tration of such agents had no effect on ischemia-induced glutamate release within the hippocampus under these experimental conditions. Based on these results, further work is needed to compare in vivo versus in vitro experime ntal results in acute and long-term treatment studies with adenosine recept or agonists and antagonists. (C) 2000 Elsevier Science B.V. All rights rese rved.