title: A new semisynthetic derivative of sauroine induces LTP in hippocampal slices and improves learning performance in the Morris Water Maze.
abstract: Two semisynthetic acetyl derivatives of the alkaloid sauroine from Huperzia saururus, monoacetyl sauroine, and diacetyl sauroine (DAS) were obtained and their chemical structures were analyzed by NMR. While monoacetyl sauroine is the typical product of acetylation, DAS is an unexpected derivative related to the keto-enol formation of sauroine. Recordings of field excitatory post-synaptic potentials from the CA1 region of rat hippocampal slices showed that only DAS acutely applied induced chemical long-term potentiation (LTP) in a dose-dependent manner with an EC50 of 1.15 ± 0.09 μM. This effect was blocked by 10 μM D(-)-2-amino-5-phosphonopentanoic acid (AP5), suggesting dependence on the NMDA receptor. DAS significantly increased NMDA receptor-dependent excitatory post-synaptic currents without affecting α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor-dependent currents. Repetitive administration of DAS improved visuo-spatial learning in the Morris Water Maze. In slices from rats tested in the Morris Water Maze, LTP resulting from electrical synaptic stimulation was 2.5 times larger than in controls. Concentration of DAS measured in the brain after repetitive administration was 29.5 μM. We conclude that slices perfused with DAS display a robust NMDA receptor-dependent chemical LTP. During chronic treatment, DAS enhances learning abilities through a metaplastic mechanism as revealed by the augmentation of LTP in slices. DAS, therefore, may be a promising compound as a nootropic therapeutic drug. A semisynthetic derivative of sauroine, diacetyl sauroine (DAS), induces chemical long-term potentiation in rat hippocampal slices increasing the NMDA receptor-dependent current. 2 mg/kg prior to each session in a Morris Water Maze (MWM) improves behavior performance. In slices prepared from the tested rats the electrical stimulation-dependent long-term potentiation (LTP) was greatly enhanced. Therefore, DAS may have potency as a nootropic drug against the memory decline.
authors.affiliation: Farmacognosia, Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina; Argentina-Instituto Multidisciplinario de Biología Vegetal (IMBIV) - CONICET, Córdoba, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: Vallejo
authors.forename: Sebastián
authors.initials: S
authors.lastname: Loyola
authors.forename: Darwin
authors.initials: D
authors.lastname: Contreras
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Ugarte
authors.forename: Diego
authors.initials: D
authors.lastname: Cifuente
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ortega
authors.forename: José L
authors.initials: JL
authors.lastname: Cabrera
authors.forename: Marc
authors.initials: M
authors.lastname: Zeise
authors.forename: Carlos
authors.initials: C
authors.lastname: Tonn
authors.forename: Mario
authors.initials: M
authors.lastname: Carreño
authors.forename: Ricardo
authors.initials: R
authors.lastname: Delgado
authors.forename: Bernardo
authors.initials: B
authors.lastname: Morales
authors.forename: Mariel
authors.initials: M
authors.lastname: Agnese
mesh_terms: D000470:Alkaloids / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000187:drug effects; D056654:CA3 Region, Hippocampal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D032501:Huperzia / Q000737:chemistry*; D017774:Long-Term Potentiation / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D018782:Maze Learning / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects; D018697:Nootropic Agents; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects
chemical_list: D000470:Alkaloids; D018697:Nootropic Agents; D016194:Receptors, N-Methyl-D-Aspartate; C535132:sauroine
keywords: learning and memory; long-term potentiation; lycopodium alkaloids; metaplasticity; sauroine acetylation; synaptic plasticity