In rats,
cyclo-L-glycyl-L-2-allylproline (NNZ-2591), a
diketopiperazine, is neuroprotective after ischemic
brain injury and also improves motor function in a rat model of
Parkinson's disease. Given
nootropic actions of
diketopiperazines, we investigated the effects of and potential role for
acetylcholine neurotransmission in
NNZ-2591 on spatial memory after
scopolamine-induced
amnesia in rats. Adult male Wistar rats were assigned to four groups: saline/water; saline/NNZ-2591;
scopolamine/water and
scopolamine/NNZ-2591. Morris Water Maze (MWM) tasks were used to determine spatial learning and memory. Thirty minutes prior to each of four daily acquisition trials, rats were intraperitoneally injected with either
scopolamine (0.5 mg/kg) or saline. Either
NNZ-2591 (30 mg/kg) or water was administered orally (gavages) 10 min after the injection. Immediately after completion of the day 4 acquisition trial a spatial probe trial was performed. The brains were then collected for immunohistochemical analysis.
Scopolamine impaired spatial learning and memory compared to saline treated group, particularly in the day 1 acquisition trial.
NNZ-2591 did not reverse this deficit, however it significantly improved memory retention by showing more time spent in the correct quadrant.
NNZ-2591 also counteracted the
scopolamine-induced up-regulation of
choline-acetyltransferase positive neurons in the striatum and similarly counteracted the increased
synaptophysin density in the hippocampus. Furthermore, a
scopolamine-independent antagonistic effect on
muscarinic M2
acetylcholine receptors was found after
NNZ-2591 treatment, supporting its modulation of
acetylcholine neurotransmission. The data suggest that
NNZ-2591 prevents
scopolamine-induced acute impairment in memory and modulation of
acetylcholine neurotransmission may be the mode of action underlying the memory improvement.