title: Anti-amnesic properties of (+/-)-PPCC, a novel sigma receptor ligand, on cognitive dysfunction induced by selective cholinergic lesion in rats.
abstract: Previous studies have reported that selective sigma-1 agonists may improve cognitive abilities in experimental animals possibly via a cholinergic mechanism. However, the issue of a direct action on to sigma-1 receptors in memory-related brain areas has been much less investigated. The newly synthetised compound methyl(1R,2S/1S,2R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropanecarboxylate [(+/-)-PPCC] has recently been shown to possess high affinity for the sigma-1 receptor where it specifically acts as an agonist. Here, the functional effects of (+/-)-PPCC were investigated in rat models of mild or severe cognitive dysfunction based on a sub-total (<or= 70-80%) or complete (>or= 90-95%) central cholinergic depletion induced by different doses of the selective immunotoxin 192 IgG-saporin injected intraventricularly. At 5-6 weeks post-surgery, the lesioned animals exhibited dose-dependent deficits in reference memory, as assessed using the Morris water maze task, whereas working memory abilities, evaluated using the radial arm water maze task, appeared equally impaired in the two dose groups. Daily treatment with (+/-)-PPCC significantly improved both reference and working memory performance in all lesioned animals but it did not affect intact or sham-lesioned subjects. In a separate test, treatment with (+/-)-PPCC reversed the learning deficits induced by the muscarinic receptor antagonist atropine sulphate in both control and mild-lesioned rats. The effect was blocked in lesioned, but not normal animals by pre-treatment with the sigma-1 antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine. The results suggest that (+/-)-PPCC may efficiently ameliorate perturbed cognitive abilities, and that these anti-amnesic effects most probably occur via a direct interaction of the compound with sigma-1 receptors.
authors.affiliation: BRAIN Centre for Neuroscience, Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Vuokko
authors.initials: V
authors.lastname: Antonini
authors.forename: Orazio
authors.initials: O
authors.lastname: Prezzavento
authors.forename: Marino
authors.initials: M
authors.lastname: Coradazzi
authors.forename: Agostino
authors.initials: A
authors.lastname: Marrazzo
authors.forename: Simone
authors.initials: S
authors.lastname: Ronsisvalle
authors.forename: Emanuela
authors.initials: E
authors.lastname: Arena
authors.forename: Giampiero
authors.initials: G
authors.lastname: Leanza
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal; D001285:Atropine; D001522:Behavior, Animal; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003521:Cyclopropanes / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005029:Ethylenediamines / Q000627:therapeutic use; D005260:Female; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists; D018697:Nootropic Agents / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D017480:Receptors, sigma / Q000037:antagonists & inhibitors; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins
chemical_list: C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D003521:Cyclopropanes; D005029:Ethylenediamines; D018727:Muscarinic Antagonists; D018697:Nootropic Agents; D010880:Piperidines; D017480:Receptors, sigma; D054789:Ribosome Inactivating Proteins, Type 1; C518986:methyl 2-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)-1-(4-methylphenyl)cyclopropanecarboxylate; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D001285:Atropine; D000076985:Saporins; D000109:Acetylcholine