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

Porto

Congreso; ISN-ESN 2023 Meeting; 2023

Sildenafil-SILD is a phosphodiesterase 5-PDE5 inhibitor approved for peripheral pathologies and is frequently misused. However, it reaches the brain, improves transmission in hippocampus-HP and raises dopamine-DA levels. Coincidently, DA increases induce memory impairments in some animal models. Objectives: 1-to evaluate the effects of SILD on HP-dependent memories, 2-to evaluate DA dependence in those effects, 3-to 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-SD. MYM also was performed 24h after SILD administration. Another group was treated with DA-D3 receptor antagonist, FAUC365 (2,5mg/kg, sc), after SILD injection 20 min before NOR training. 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 time exploring novel arm in MYM (two-way ANOVA, p<0,01) and discrimination index in NOR performance. The SILD-induced deficits in NOR were prevented by FAUC365 (one-way ANOVA, p<0,005). SILD enhanced % of freezing after FC and 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, reducing performance in non-aversive memory tests but improving the aversive ones. These effects reveal the importance of considering SILD central effects when they are not required, and support the experimental evaluation of active PDE5 inhibitors without brain distribution.