title: Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimer's disease: a translational overview.
abstract: Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Since both cAMP and cGMP signaling are essential in a variety of cellular functions, including neuroplasticity and neuroprotection, PDE-Is are receiving increased attention as possible targets for treatment of age-related cognitive decline as well as Alzheimer's disease (AD). In this review we will give a translational overview of the preclinical and clinical data on PDE-Is and cognition enhancement focusing on aging and AD. PDE2, 4 and 5 inhibitors improved memory performance in both aged animals and models of AD. Treatment with a PDE3-I or PDE7-I has not been tested in aged animals yet, but in mouse models of AD both PDE-Is improved memory performance. Unfortunately, there are no peer-reviewed studies on the effects of PDE-I treatment in aged human subjects except the possible positive effect on memory impairment of the PDE1-I vinpocetine. Three other types of PDE-Is have been tested on cognition in mild to moderate AD patients: the PDE3-I cilostazol is being tested as a co-treatment to the acetylcholinesterase inhibitor donepezil, but with inconsistent results; the PDE4-I MK-0952 has been tested, although the outcome has not been disclosed yet; and the PDE9-I PF- 04447943 was reported to have no effects on cognition. Obviously, the demonstration of clinical proof of concept for cognition enhancing effects of PDE-Is and the generation of isoform selective PDE-Is are the final hurdles to overcome in developing safe and efficacious novel PDE-Is for the treatment of age-associated cognitive decline or AD.
authors.forename: P R A
authors.initials: PR
authors.lastname: Heckman
authors.forename: C
authors.initials: C
authors.lastname: Wouters
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands. jos.prickaerts@maastrichtuniversity.nl.
authors.forename: J
authors.initials: J
authors.lastname: Prickaerts
mesh_terms: D000375:Aging / Q000187:drug effects*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000517:prevention & control*; D006801:Humans; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D057170:Translational Research, Biomedical
chemical_list: D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases