title: NNZ-2591, a novel diketopiperazine, prevented scopolamine-induced acute memory impairment in the adult rat.
abstract: 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.
authors.affiliation: Liggins Institute, The University of Auckland, Auckland, New Zealand. j.guan@auckland.ac.nz
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Linden
authors.initials: L
authors.lastname: Dale-Gandar
authors.forename: Steve
authors.initials: S
authors.lastname: Hodgkinson
authors.forename: Mark H
authors.initials: MH
authors.lastname: Vickers
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D054659:Diketopiperazines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D012601:Scopolamine; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002795:Choline O-Acetyltransferase; D054659:Diketopiperazines; D005968:Glutamate Decarboxylase; D018696:Neuroprotective Agents; D010456:Peptides, Cyclic; D043585:Receptor, Muscarinic M2; D018091:Receptors, AMPA; D012601:Scopolamine; D016708:Synaptophysin; D014446:Tyrosine 3-Monooxygenase; C540261:cyclo-L-glycyl-L-2-allylproline