Sildenafil Rescues the Age-related Impairment of Synaptic Plasticity, Memory and CREB Phosphorylation in a Physiological Mouse Model of Aging

Objectives: Because the cyclic nucleotide cascade is required for the integrity of synaptic function and memory, and it is down-regulated during aging and neurodegenerative disorders, we aimed to investigate whether an increase of cGMP levels might be useful to rescue age-related synaptic and memory deficits in mice. Methods: We treated C57Bl/6J wild type mice with the phosphodiesterase 5 inhibitor sildenafil or vehicle at 3-5 months of age (young mice) or at 26-30 months of age (old mice). After 3-weeks treatment, animals underwent electrophysiological recordings, behavioral experiments, and evaluation of phophorylated c-AMP responsive element-binding protein (p-CREB) by western blot and immunohistochemistry. Results: Treatment with sildenafil ameliorated long-term potentiation in hippocampal slices of old mice. Moreover, it rescued the age-related spatial learning and reference memory tested by the Morris Water Maze, and recognition memory tested by the Object Recognition Test. Finally, sildenafil restored p-CREB, which is known to be crucial for synaptic plasticity and memory. Conclusions: Our data suggest that the inhibition of phosphodiesterase-5 might be beneficial for the treatment of age-related cognitive dysfunction in a physiological mouse model of aging.