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Sub-efficacious doses of phosphodiesterase 4 and 5 inhibitors improve memory in a mouse model of Alzheimer's disease.

Abstract：

:Cyclic nucleotides cAMP and cGMP cooperate to ensure memory acquisition and consolidation. Increasing their levels by phosphodiesterase inhibitors (PDE-Is) enhanced cognitive functions and rescued memory loss in different models of aging and Alzheimer's disease (AD). However, side effects due to the high doses used limited their application in humans. Based on previous studies suggesting that combinations of sub-efficacious doses of cAMP- and cGMP-specific PDE-Is improved synaptic plasticity and memory in physiological conditions, here we aimed to study whether this treatment was effective to counteract the AD phenotype in APPswe mice. We found that a 3-week chronic treatment with a combination of sub-efficacious doses of the cAMP-specific PDE4-I roflumilast (0.01 mg/kg) and the cGMP-specific PDE5-I vardenafil (0.1 mg/kg) improved recognition, spatial and contextual fear memory. Importantly, the cognitive enhancement persisted for 2 months beyond administration. This long-lasting action, and the possibility to minimize side effects due to the low doses used, might open feasible therapeutic strategies against AD.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

Gulisano W,Tropea MR,Arancio O,Palmeri A,Puzzo D

doi

10.1016/j.neuropharm.2018.06.002

subject

Has Abstract

pub_date

2018-08-01 00:00:00

pages

151-159

eissn

0028-3908

issn

1873-7064

pii

S0028-3908(18)30276-4

journal_volume

138

pub_type

杂志文章

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