title: Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion.
abstract: Sigma-1 receptor agonists have recently attracted much attention as potential therapeutic drugs for cognitive and affective disorders, however, it is still unclear whether they act via modulation of transmitter release or activation of sigma-1 receptors in memory-related brain regions. In the present study,we have investigated the anti-amnesic and neuroprotective actions of the compound (-)-methyl (1S,2R)-2-{[1-adamantyl(methyl)amino]methyl}-1-phenylcyclopropane-carboxylate) [(-)-MR22],a selective sigma-1 receptor agonist able to protect cultured cortical neurons from amyloid toxicity. To this aim, cognitive deficits, cholinergic loss, and amyloid peptide accumulation were obtained in the rat by simultaneous injections of a selective immunotoxin and pre-aggregated amyloid peptide into the basal forebrain and the hippocampus, respectively. At about five–six weeks post-lesion, the double-lesioned animals exhibited dramatic deficits in spatial learning and memory, whereas animals with single injections of either compound were not or only marginally affected, in spite of equally severe cholinergic loss oramyloid deposition. Administration of (-)-MR22 appeared to reverse cognitive impairments in double lesioned animals, whereas pre-treatment with the selective sigma-1 antagonist BD1047 abolished this effect. Moreover, (-)-MR22 normalized the levels of cell-associated amyloid-β protein precursor (AβPP) in the neocortex and hippocampus, thus sustaining a non-amyloidogenic AβPP processing. By contrast, treatment with (-)-MR22 produced no effects whatsoever in intact animals. Thus, sigma-1 receptor agonists such as (-)-MR22 may ameliorate perturbed cognitive abilities and exert a protective action onto target neurons, holding promises as viable tools for memory enhancement and neuroprotection.
authors.affiliation: B.R.A.I.N. Centre for Neuroscience, Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Vuokko
authors.initials: V
authors.lastname: Antonini
authors.forename: Agostino
authors.initials: A
authors.lastname: Marrazzo
authors.forename: Giulio
authors.initials: G
authors.lastname: Kleiner
authors.forename: Marino
authors.initials: M
authors.lastname: Coradazzi
authors.forename: Simone
authors.initials: S
authors.lastname: Ronsisvalle
authors.forename: Orazio
authors.initials: O
authors.lastname: Prezzavento
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ronsisvalle
authors.forename: Giampiero
authors.initials: G
authors.lastname: Leanza
mesh_terms: D000110:Acetylcholinesterase; D000218:Adamantane / Q000031:analogs & derivatives / Q000627:therapeutic use; D000682:Amyloid / Q000633:toxicity*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity; D001930:Brain Injuries / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy*; D018678:Cholinergic Agents / Q000378:metabolism*; D003521:Cyclopropanes / Q000627:therapeutic use; D005260:Female; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000209:etiology; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D017480:Receptors, sigma / Q000819:agonists*; D054789:Ribosome Inactivating Proteins, Type 1 / Q000633:toxicity; D000076985:Saporins; D013997:Time Factors; D000097605:Sigma-1 Receptor
chemical_list: D000110:Acetylcholinesterase; D000218:Adamantane; D000682:Amyloid; D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D018678:Cholinergic Agents; D003521:Cyclopropanes; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017480:Receptors, sigma; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D000097605:Sigma-1 Receptor; C085696:192 IgG-saporin; C561091:2-((1-adamantyl(methyl)amino)methyl)-1-phenylcyclopropanecarboxylic acid; C074636:amyloid beta-protein (25-35)