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Behav Brain Res. 2013 Mar 1;240:11-20. doi: 10.1016/j.bbr.2012.10.060. Epub 2012 Nov 19.

Inhibition of phosphodiesterase-5 rescues age-related impairment of synaptic plasticity and memory.

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Department of Bio-Medical Sciences - Section of Physiology, University of Catania, Catania, 95125, Italy.


Aging is characterized by a progressive cognitive decline that leads to memory impairment. Because the cyclic nucleotide cascade is essential for the integrity of synaptic function and memory, and it is down-regulated during aging and in neurodegenerative disorders, we investigated whether an increase in cGMP levels might rescue age-related synaptic and memory deficits in mice. We demonstrated that acute perfusion with the phosphodiesterase-5 inhibitor sildenafil (50 nM) ameliorated long-term potentiation in hippocampal slices from 26-30-month-old mice. Moreover, chronic intraperitoneal injection of sildenafil (3mg/kg for 3 weeks) improved age-related spatial learning and reference memory as tested by the Morris Water Maze, and recognition memory as tested by the Object Recognition Test. Finally, sildenafil restored central cAMP responsive element-binding protein (CREB) phosphorylation, which is crucial for synaptic plasticity and memory. Our data suggest that inhibition of phosphodiesterase-5 may be beneficial to treat age-related cognitive dysfunction in a physiological mouse model of aging.

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