PROTECTIVE EFFECT OF ADENOSINE AND A NOVEL XANTHINE DERIVATIVE PROPENTOFYLLINE ON THE CELL-DAMAGE AFTER BILATERAL CAROTID OCCLUSION IN THE GERBIL HIPPOCAMPUS

The role of adenosine in the development of ischemia induced pathological changes has been examined in Mongolian gerbils. A dramatic increase in the concentrations of adenosine, inosine and hypoxanthine was detected by microdialysis in the dorsal part of hippocampus and in the striatum immediately after 5 min bilateral occlusion of the carotid arteries. From a resting value of about 0.5 μM the concentration of adenosine increased to more than 10 μM. The adenosine levels became normalized within 30 min after ischemia. Inosine and hypoxanthine levels were higher and they increased and also returned towards control somewhat later than adenosine. A second occlusion resulted in a similar but somewhat smaller increase in purine levels. Carotid occlusion for up to 12 min had no major, lasting effect on the binding to adenosine A1-receptors in the CA-regions of the hippocampus, as determined by autoradiography. Neuronal and vascular changes (degeneration of neurons, mitochondrial destruction and ribosomal disaggregation, astroglial oedema) due to ischemia (3-12 min, followed by 48 h recirculation) was studied with light and electron microscopy in the selectively vulnerable CA1 area of hippocampus. In one series of experiments the adenosine antagonist theophylline (20 mg/kg i.p.), given 15 min prior to a 5 min occlusion, significantly enhanced the ischemia induced changes. In another experiment the adenosine uptake inhibitor propentofylline (HWA 285, 10 mg/kg), injected 15 min before a 12 min carotid occlusion, reduced the neuronal (90%) and astroglial changes (84%) due to ischemia. The results provide further evidence that adenosine could play a role as an endogenous protective substance in ischemia by showing that ischemia leads to a massive increase in extracellular adenosine concentration with little change in adenosine receptors and by the demonstration at the ultrastructural level that the adenosine antagonist theophylline aggravates and that propentofylline, a drug known to raise levels of adenosine, decreases ischemia induced neuronal and vascular degeneration. © 1990.