Targeting phosphodiesterase 4 as a therapeutic strategy for cognitive improvement

[Display omitted] •PDE4, abundantly expressed in CNS, hydrolyzes cAMP involved in cognitive functions.•Inhibition of PDE4 is beneficial to counteract cognitive deficits.•Development of PDE4 inhibitors is hindered by dose-limiting adverse effects.•Targeting specific PDE4 subtypes may be feasible for cognitive improvement. Phosphodiesterase 4 (PDE4), the largest member of PDE family, is highly expressed in mammalian brain. It selectively hydrolyzes the second messenger cyclic adenosine monophosphate (cAMP), a correlate of brain functions including learning, memory and cognitive abilities. Its inhibition is beneficial to counteract cognitive deficits. Thus, targeting PDE4 may be a viable strategy for cognitive improvement. Currently, many PDE4 inhibitors have been discovered but with a great hurdle in clinical development due to adverse effects such as emesis. Analysis of PDE4 subtypes and discovery of subtype specific regulators indicate therapeutic benefits with improved safety in preclinical and clinical models. Herein, we summarize PDE4 structure, describe PDE4 mediated signaling pathways, review the role of individual PDE4 subtypes and discuss the development of PDE4 inhibitors for cognitive improvement, trying to give an insight into the strategy for cognitive improvement with PDE4 inhibitors in future.