SILDENAFIL DUAL EFFECTS ON MEMORY SUPPORT THE SEARCH FOR NEW DERIVATIVES WITH RESTRICTED ACCESS TO THE BRAIN

CONSTANTIN MF; MARCOTTI A; ARTUR DE LA VILLARMOIS, E; PONCE BETI MF; CALFA G; QUEVEDO, A; PÉREZ MF

Congreso; Reunión conjunta de sociedades de biociencias 2021; 2021

Sildenafil (SILD) is a drug widely used in clinical practice for its inhibitory effects on phosphodiesterase type 5 (PDE-5), mainly used for peripheral pathologies. Although, it crosses the blood brain barrier. Previous results indicated that systemic acute SILD administration facilitated hippocampal (HP) long-term potentiation, a synaptic plasticity phenomenon that underlies some types of learning and memory processes. Objectives: to evaluate the effects of SILD on acquisition of HP-dependent memories, and to identify the structure activity relationships driving SILD interaction with PDE-5 and to further search for derivatives with higher hydrophilicity able to restrict its passage to the brain while maintaining or improving their inhibitory activity. Material and methods: male Wistar rats were administered with an acute SILD dose 2 h before exposure to novel object recognition (NOR) test, modified Y-maze, step-down and contextual fear conditioning. Twenty-four hours later the memory expression was evaluated. Also, hydrophilic SILD derivatives were identified by in silico methods. Results: SILD enhanced the % of freezing after weak fear conditioning (unpaired t-test) and the latency to step-down (Mann Whitney test). Surprisingly, it reduced novel object (unpaired t-test) and novel arm exploration (two-way ANOVA) when compared to controls. On the other hand, molecular docking identified SILD-PDE-5 pharmacophoric contacts, with some hydrophilic derivatives of SILD already described in the bibliography being docked within the PDE-5 binding site. Conclusions: these results revealed that SILD divergently contribute to HP-dependent memory formation, probably depending on the stimulus nature and participation of other brain structures. Furthermore, these results support the experimental evaluation of SILD derivatives that could avoid these and other possible unwanted central effects, but promising maintenance of their inhibitory power on PDE-5 at the peripheral level.