Sildenafil effects on memory and search for new derivatives with restricted access to brain

CONSTANTÍN, M.F.; MARCONETTI, A.; ARTUR DE LA VILLARMOIS, E.; PONCE BETI, F.; CALFA, G.; QUEVEDO, M.A.; PÉREZ, M.F.

Congreso; Reunión Conjunta SAIC, SAI, AAFE, NANOMED.ar 202; 2021

Sildenafil (SILD) is a drug widely used in clinical practice for its inhibitory effects on phosphodiesterase type 5 (PDE-5), enhancing the signaling pathway activated by nitric oxide (NO/GC /GMP). SILD crosses the blood brain barrier, and PDE-5 is expressed in the brain. In the hippocampus (HP), NO increases glutamate release, which is essential for long-term potentiation maintenance, a phenomenon of synaptic plasticity that underlies the formation of learning and memory. On the other hand, taking into account that the current clinical uses of SILD are for peripheral pathologies, these are unwanted side effects. For these reasons, the objective of this work is to evaluate the effect of SILD on the acquisition of HP-dependent memories, identify the structure activity relationships driving its interaction with PDE5 and further searching for derivatives with higher hydrophilicity able to restrict its passage to the brain while maintaining or improving their inhibitory activity. For this purpose, male Wistar rats were administered with an acute dose of SILD or saline before training in novel object recognition (NOR) test, modified Y-maze, step-down and contextual fear conditioning, and 4 or 24 hours later the memory acquisition was evaluated. SILD-PDE-5 pharmacophoric contacts were identified by molecular docking, with some hydrophilic derivatives of SILD already described in the bibliography being docked within the PDE-5 binding site. Our results showed that animals administered with SILD manifest the memory of fear more easily than the control animals in contextual fear conditioning and step-down, but a lower rate of exploration of the novel object or the novel arm, in the NOR and modified Y-maze respectively. In this respect, the hydrophilic SILD derivatives identified by in silico methods may avoid side effects at the central level and maintain their inhibitory power on PDE-5 at the peripheral level promising, thus supporting their experimental evaluation.