A new semisynthetic derivative of sauroine induces LTP in hippocampal slices and improves learning performance in the Morris Water Maze

• Published in: Journal of neurochemistry Vol. 129; no. 5; pp. 864 - 876
• Main Authors: Vallejo, Mariana, Loyola, Sebastián, Contreras, Darwin, Ugarte, Gonzalo, Cifuente, Diego, Ortega, Gabriela, Cabrera, José L., Zeise, Marc, Tonn, Carlos, Carreño, Mario, Delgado, Ricardo, Morales, Bernardo, Agnese, Mariel
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2014
• Subjects: Alkaloids - pharmacokinetics; Alkaloids - pharmacology; Animal memory; Animals; Brain; Brain - metabolism; CA1 Region, Hippocampal - drug effects; CA3 Region, Hippocampal - drug effects; Dose-Response Relationship, Drug; Drug therapy; Electrophysiological Phenomena - drug effects; Excitatory Postsynaptic Potentials - drug effects; Hippocampus - drug effects; Huperzia; Huperzia - chemistry; Learning; learning and memory; Long-Term Potentiation - drug effects; long‐term potentiation; lycopodium alkaloids; Magnetic Resonance Spectroscopy; Maze Learning - drug effects; metaplasticity; Neurochemistry; Neuronal Plasticity - drug effects; Nootropic Agents; Psychomotor Performance - drug effects; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - drug effects; Rodents; sauroine acetylation; Saururus; Structure-Activity Relationship; Synapses - drug effects; synaptic plasticity; sauroine acetylation; synaptic plasticity; learning and memory; metaplasticity; lycopodium alkaloids; long-term potentiation
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12685

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. 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.