Effect of denbufylline in passive avoidance trials in gerbils, following transiet forebrain ischaemia, and in mice

Abstract

Denbufylline (1,3-di-n-butyl-7-[2-oxopropyl]-xanthine) has been examined in passive avoidance trials in gerbils, following transient forebrain ischaemia, and in mice. Animals were conditioned to avoid a darkened compartment by means of a foot shock received upon entering. Learning and memory were tested 24 hr later by replacing the animals in the box and measuring the latency to enter the dark compartment. In gerbils, transient (5 min) forebrain ischaemia was induced 24 hr prior to training by bilateral closure of the carotid arteries. Controls were sham-ligated. All gerbils received seven subcutaneous injections of saline or denbufylline, the first during forebrain ischaemia or immediately following sham-ligation, and the rest 3, 6, 24, 27, 30, and 48 hr later. Mice received one subcutaneous injection of saline or denbufylline immediately after training. The results show that denbufylline enhances memory formation in mice after a mild learning stimulus and recollection in gerbils following forebrain ischaemia.

The ability of denbufylline to inhibit cyclic nucleotide phosphodiesterase and its affinity for adenosine receptors and the adenosine re‐uptake site

“…These data support the hypothesis that selective inhibitors of the different Ca2"-independent low Km cyclic AMP phosphodiesterases can selectively affect tissue function. Denbufylline improves recollection of information in mice and gerbils in which a learning or memory deficit has been induced by forebrain ischaemia (Nicholson et al, 1988) and, in this regard, cyclic AMP has been postulated to influence synaptic efficacy and memory formation (Goelet et al, 1986;Gray & Johnston, 1987). Consequently, selective inhibition of a cerebral cyclic AMP phosphodiesterase may account for the enhancing effect of denbufylline on learning and memory.…”

“…Selective adenosine receptor antagonists, such as theophylline and caffeine, reduce cerebral blood flow (Mathew et al, 1983;Grome & Stefanovich, 1986). Denbufylline, on the other hand, increases the blood flow and oxygen tension of the oligaemic cortex (Nicholson & Angersbach, 1986) at doses which enhance retention of information (Nicholson et al, 1988), which indicates that it is not effectively antagonising the effects of adenosine at these doses. Further evidence for this is that denbufylline, at doses greater than those which enhance learning or memory formation, neither potentiates nor attenuates ischaemia-induced neuronal damage (Jukna & Nicholson, unpublished information).…”

“…This investigation was carried out to characterise further the activity profile of the alkylxanthine denbufylline (1,3-di-n-butyl-742'-oxopropyl)-xanthine). This compound has previously been shown to increase the oxygen tension (Po2) and function of partially ischaemic skeletal muscle (Angersbach & Ochlich, 1984), to enhance the retention of information (Nicholson et al, 1988) and to improve the flow properties of blood (Jukna & Nicholson, 1987). It is presently undergoing clinical evaluation in dementia (see existing data generated by O'Connolly et al, 1986;1988).…”