ARE SILDENAFIL DUAL EFFECTS ON MEMORY RELATED TO THE ACTIVATION OF DOPAMINE SYSTEM? IMPORTANCE OF SEARCHING FOR NEW DERIVATIVES WITH RESTRICTED ACCESS TO THE BRAIN.

CONSTANTIN MF; PONCE BETI MF; SOFÍA DE LA FUENTE; MARCOTTI A; RIBONE S; QUEVEDO, A; MARIELA F. PÉREZ.

Mar del Plata

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2022; 2022

Sildenafil (SILD) is the most clinically phosphodiesterase type 5 (PDE5) inhibitor used for peripheral pathologies, but it is misused without prescription. SILD reaches the brain and is proposed as a cognitive enhancer for pathologies such as Alzheimer’s disease. In fact, it improves transmission in the hippocampus (HP), a brain region involved in learning and memory, and also raises dopamine (DA) levels. Coincidently, DA increases may induce memory impairments in some animal models. Nevertheless, SILD central effects are not fully described in healthy conditions. Objectives: 1- to evaluate the effects of SILD on HP-dependent memories, 2- to evaluate the DA dependence of SILD-induced memory deficits, 3- search for SILD derivatives with higher hydrophilicity and preserved activity. Material and methods: male Wistar rats (55 days old) received a SILD dose (5 mg/kg, i.p.) 2 h before training in novel object recognition-NOR, Barnes-BM, Y-maze-YM or modified YM. Other group was treated with the DA-D3 receptor antagonist, FAUC365 (3mg/Kg, s.c.), 10 min before NOR training. Memory expression was evaluated accordingly each test. Also, hydrophilic SILD derivatives were identified by in silico methods. Results: SILD reduced NOR (p<0,05 unpaired t-test) and modified YM (two-way ANOVA) performance, while no changes were observed in BM or YM. Experiments with FAUC365 are still in progress. On the other hand, molecular docking identified SILD-PDE5 pharmacophoric contacts with some hydrophilicderivatives of SILD described in the bibliography. Conclusions: SILD impairs HP-dependent memory formation, probably by increases in DA activity. These effects reveal the importance of considering the SILD central effects, when it is used under prescription or recreationally by young subjects. Altogether, these results support the experimental evaluation of peripheral-acting SILD derivatives that could avoid these and other possible unwanted central effects.