Cognitive processing: the role of phosphodiesterase-5 as new target

The cyclic nucleotides, cAMP and cGMP, are second messengers that regulate signal transduction in various biological systems, including the central nervous system where they are key molecules in synaptic plasticity and memory. Their levels are maintained thanks to a balance between production, carried out by adenylate and guanylate cyclases, and destruction, carried out by phosphodiesterases (PDEs). Over the last few years an increasing number of studies focused on PDEs due to the potential use of these enzymes as targets of drugs that can regulate the levels of cyclic nucleotides. PDE inhibitors (PDE-Is) are so far indicated only to treat erectile dysfunction, pulmonary hypertension and, more recently, chronic obstructive pulmonary disease. However, several evidences indicate the potential therapeutic role of PDE-Is in nervous system disorders. Cyclic nucleotide cascades are down-regulated during aging and in neurodegenerative disorders. Moreover, an interaction between cyclic nucleotides and beta-amyloid (Aβ), a key pathogenic factor in Alzheimer’s Disease (AD), as been showed in both physiological and pathological conditions. In the last few years, preclinical studies have shown that an increase of cAMP and cGMP by specific PDE4- and PDE5-Is might be beneficial against synaptic and memory deficits. In particular, our group have demonstrated that the increase in cGMP levels induced by a treatment with the PDE5-I sildenafil (Viagra) was able to rescue synaptic and memory deficits in animal models of AD (APP/PS1 mice) and aging restoring CREB phosphorylation. Moreover, we have recently studied the interactions between cAMP/PKA and cGMP/PKG pathway in synaptic plasticity and memory and demonstrated that an association of sub-efficacious doses of PDE4- and PDE5-Is might improve cognition in healthy and aged mice.