Selective phosphodiesterase inhibitors: a promising target for cognition enhancement

Abstract

Rationale One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer's disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or cAMP. Objective The aim of this review was to provide an overview of the effects of phosphodiesterase inhibitors (PDE-Is) on cognition, the possible underlying mechanisms, and the relationship to current theories about memory formation. Materials and methodsStudies of the effects of inhibitors of different PDE families (2, 4, 5, 9, and 10) on cognition were reviewed. In addition, studies related to PDE-Is and blood flow, emotional arousal, and long-term potentiation (LTP) were described. Results PDE-Is have a positive effect on several aspects of cognition, including information processing, attention, memory, and executive functioning. At present, these data are likely to be explained in terms of an LTP-related mechanism of action. Conclusion PDE-Is are a promising target for cognition enhancement; the most suitable candidates appear to be PDE2-Is or PDE9-Is. The future for PDE-Is as cognition enhancers lies in the development of isoform-specific PDE-Is that have limited aversive side effects.

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

“…In addition, PDEs may be targeted for cognitive enhancement, and inhibitors of PDEs have proven to be useful experimental tools in exploring mechanisms of learning and memory Prickaerts et al, 2004). Selective PDE inhibitors of at least five types, inhibitors of PDE2 (Boess et al, 2004;Rutten et al, 2007b), PDE4 (Barad et al, 1998;Rutten et al, 2006), PDE5 (Devan et al, 2004;Rutten et al, 2005), and PDE9 (van der Staay et al, 2008) have all been shown to enhance memory in different behavioral paradigms and in different species (for review see Reneerkens et al, 2009). This study investigated the effects of PDE inhibition on spatial memory in the OLT.…”

Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

“…There are 11 different families of PDEs that vary in their substrate specificity, kinetic properties, modes of regulation, intracellular localization, and tissue expression patterns (6)(7)(8). PDE 10A (PDE10A) is a dual-substrate PDE that degrades both cAMP and cGMP.…”

Reducing Neuroinflammation in Psychiatric Disorders: Novel Target of Phosphodiesterase 4 (PDE4) and Developing of the PDE4 Inhibitors

“…Consistent with this hypothesis, the previous studies have demonstrated that rolipram reduces neuroinflammation and promotes axonal regeneration and functional recuperation following spinal cord injury [96][97][98]; [62]. More evidence have shown that PDE4 inhibitor rolipram reduces the production of proinflammatory cytokines and modulates the activity of cAMP-mediated signaling and thus regulates CREB phosphorylation and the downstream efectors [99]; [62,68], showing that potential PDE4 inhibitors may be suitable to antagonize psychiatric disorders. Unfortunately, the development of PDE4 inhibitor rolipram for therapeutic purposes has been hindered by side efects, such as emesis [100,101].…”