PDE4 as a target for cognition enhancement

Abstract

Introduction The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs. Areas covered PDE4 is the largest of the eleven mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation. Expert opinion PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors.

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

“…1994; Blokland et al, 2006;Ghavami et al, 2006;Richter et al, 2013). Regulation of cAMP levels in brain by PDE4 modulates one of the fundamental pathways underlying synaptic plasticity, longlasting late-phase long-term potentiation, via activation of protein kinase A and cAMP response element-binding protein (Slack and Pockett, 1991;Frey et al, 1993;Matthies and Reymann, 1993).…”

Intracellular Membrane Association of the Aplysia cAMP Phosphodiesterase Long and Short Forms via Different Targeting Mechanisms

“…Phosphodiesterases (PDEs) 6 are important regulators of signal transduction mediated by cAMP, which is a key signaling molecule modulating physiological functions, including learning and memory (1)(2)(3). Among the 11 families of PDEs, PDE4 degrades cAMP specifically, is a four-gene family (A, B, C, and D) in mammalian cells, and is important for various functions, including cognition (3).…”

“…Among the 11 families of PDEs, PDE4 degrades cAMP specifically, is a four-gene family (A, B, C, and D) in mammalian cells, and is important for various functions, including cognition (3). The role of PDE4 in synaptic plasticity has been investigated in various organisms, including Drosophila, Aplysia, and mammals.…”

Protein–protein interactions of PDE4 family members — Functions, interactions and therapeutic value

“…In addition to COPD and psoriasis for whose treatment PDE4 inhibitors are already approved (see above) there are several further major diseases associated with deregulation of PDE4 enzymes. Amongst others cognitive enhancers [59] and asthma drugs [60] are currently being develop. They all target enzyme activities.…”