SILDENAFIL DUAL EFFECTS ON MEMORY. SEARCH FOR A PHARMACODYNAMIC MODEL FOR DERIVATIVES WITH RESTRICTED ACCESS TO THE BRAIN.

Oporto

Congreso; ISN-ESN 2023 Meeting; 2023

International Society for Neurochemistry

Sildenafil-SILD is a phosphodiesterase 5-PDE5 inhibitor used for peripheral pathologies. However, it reaches the brain, improves transmission in the hippocampus-HP and raises dopamine-DA levels. Coincidently, DA increases may induce memory impairments in some animal models. 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 (50-55 days old) received a SILD dose (5mg/kg, ip) 2h before training in novel object recognition-NOR, modified Y-maze-MYM, contextual fear conditioning-FC or step-down test-SD. MYM also was performed 24h after SILD dose. Another group was treated with the DA-D3 receptor antagonist, FAUC365 (2,5mg/kg, sc), after SILD injection and 20 min before NOR training. Memory expression was evaluated. On the other hand, SILD, compounds 8, 13f and 6a were molecular docked with two different models of PDE5 receptor. The best resulting conformations of each ligand were subjected to molecular dynamics procedures and interaction energy decomposition analysis. Results: SILD reduced the time exploring the new arm in MYM (two-way ANOVA, p<0,01) and the discrimination index in NOR performance, but the SILD-induced deficit in NOR is reversed by FAUC365 (one-way ANOVA, p<0,005). SILD enhanced the % of freezing after FC and the latency to SD (two-way ANOVA, p<0,05). The energetic analysis showed that all the derivatives establish similar interactions with PDE5 residues, but the active compounds (SILD, 8, 13a) interact with two or more of the residues that make up the most polar pocket of the PDE5 cavity, with significant energy. Conclusions: SILD divergently contributes to HP-dependent memory formation. These effects reveal the importance of considering SILD central effects, and support the experimental evaluation of active PDE5 inhibitors that prevent their distribution in the brain, such as those identified in this work.