Aildenafil citrate with superior PDE5 selectivity ameliorates cognitive and behavioral impairments in APP/PS1 Alzheimer's disease mice: a preclinical phenotypic study.

INTRODUCTION

Alzheimer's disease (AD) imposes a significant global healthcare burden, and current available pharmacotherapies provide limited therapeutic benefits. Disrupted phosphodiesterase 5 (PDE5) signaling has been implicated in the pathogenesis of AD and other neurodegenerative disorders, positioning PDE5 inhibitors (PDE5Is) as a promising therapeutic strategy for AD treatment. This study evaluated the preclinical therapeutic potential of aildenafil citrate (AC), a selective PDE5I approved in China for the treatment of erectile dysfunction (ED), in AD treatment.

METHODS

Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations were integrated to explore the molecular mechanisms of aildenafil. The APP/PS1 transgenic mouse model of AD was employed to assess the in vivo efficacy of AC through behavioral, pathological, and oxidative assessments.

RESULTS

In silico analyses indicated that aildenafil exhibited a higher predicted affinity through a strengthened electrostatic network anchored by key bidentate hydrogen bonds with Gln817 and enhanced π-π stacking interactions with Phe820. Behavioral assessments, including the Barnes maze and Open field tests, demonstrated that AC significantly ameliorates cognitive dysfunction and anxiety-like impairments. Pathological examinations revealed improved hippocampal morphology, upregulated neprilysin (NEP) expression, and reduced Aβ accumulation. The decreased malondialdehyde (MDA) levels further suggested a potential attenuation of systemic oxidative stress and provided preliminary support for further investigation into its effects on central redox status.

CONCLUSION

These findings offer an initial phenotypic characterization of AC in an AD mouse model, underscoring the need for comprehensive mechanistic studies to fully evaluate its potential as a repurposed AD therapeutic candidate.