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.
Keywords: cAMP, cGMP, dementia, long-term potentiation, neurogenesis, PDE, rolipram, sildenafil.
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