Phosphodiesterase Inhibitors for Cognitive Enhancement

Rose, Greg; Hopper, Allen T.; Vivo, Michael De; Tehim, Ashok

doi:10.2174/138161205774370799

Cited by 111 publications

(74 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These studies led to the identification of a number of PDE subfamilies as promising targets for memory improvement, in specific the PDE1, PDE2, PDE4, PDE5, and PDE9 subtypes. In this study, we focused on cAMP-selective PDE4 (Barad et al, 1998;Rose et al, 2005;Rutten et al, 2007a;Zhang et al, 2005), cGMPselective PDE5 (Prickaerts et al, 2004;Rutten et al, 2005), and PDE2, which hydrolyzes both cAMP and cGMP (Boess et al, 2004;Rutten et al, 2007b). It has been suggested that the cognition-enhancing effects of PDE inhibitors are related to activation of cAMP/protein kinase A (PKA)/ cAMP responsive element-binding protein (CREB) and cGMP/protein kinase G (PKG)/CREB signaling pathways Reneerkens et al, 2009;Rutten et al, 2007b), which are both associated with late-phase LTP (L-LTP).…”

Section: Introductionmentioning

confidence: 99%

Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

Bollen

Puzzo

Rutten

et al. 2014

Neuropsychopharmacol

102

View full text Add to dashboard Cite

Memory consolidation is defined by the stabilization of a memory trace after acquisition, and consists of numerous molecular cascades that mediate synaptic plasticity. Commonly, a distinction is made between an early and a late consolidation phase, in which early refers to the first hours in which labile synaptic changes occur, whereas late consolidation relates to stable and long-lasting synaptic changes induced by de novo protein synthesis. How these phases are linked at a molecular level is not yet clear. Here we studied the interaction of the cyclic nucleotide-mediated pathways during the different phases of memory consolidation in rodents. In addition, the same pathways were studied in a model of neuronal plasticity, long-term potentiation (LTP). We demonstrated that cGMP/protein kinase G (PKG) signaling mediates early memory consolidation as well as early-phase LTP, whereas cAMP/protein kinase A (PKA) signaling mediates late consolidation and late-phase-like LTP. In addition, we show for the first time that early-phase cGMP/PKG signaling requires late-phase cAMP/PKA-signaling in both LTP and long-term memory formation.

show abstract

Section: Introductionmentioning

confidence: 99%

Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

Bollen

Puzzo

Rutten

et al. 2014

Neuropsychopharmacol

102

View full text Add to dashboard Cite

show abstract

“…PDE inhibitors present a novel therapeutic approach with which to arrest cognitive decline (Gong et al, 2004;Vitolo et al, 2002) or possibly reverse the decline with cognition enhancement Halene and Siegel 2007;Menniti et al, 2006;Rutten et al, 2008). Three promising targets through which memory improvement may be effected are cAMP-selective PDE4 (Barad et al, 1998;Rose et al, 2005;Rutten et al, 2007a;Zhang et al, 2005); cGMP-selective PDE5 (Prickaerts et al, 2004;Rutten et al, 2005); and PDE2, which hydrolyzes both cAMP and cGMP (Boess et al, 2004;Rutten et al, 2007b;Van Donkelaar et al, 2008). Evidence is accumulating that second messenger molecules, cGMP and cAMP, are important in memory processes in general and long-term potentiation in particular (Bach et al, 1999;Bernabeu et al, 1996;Bourtchouladze et al, 1998;Frey et al, 1993;Lu et al, 1999;Prickaerts et al, 2002a;Son et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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

Rutten

Donkelaar

Ferrington

et al. 2009

Neuropsychopharmacol

113

View full text Add to dashboard Cite

Phosphodiesterase (PDE) inhibitors prevent the breakdown of the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP), and are currently studied as possible targets for cognitive enhancement. Earlier studies indicated beneficial effects of PDE inhibitors in object recognition. In this study we tested the effects of three PDE inhibitors on spatial memory as assessed in a place and object recognition task. Furthermore, as both cAMP and cGMP are known vasodilators, the effects of PDE inhibition on cognitive functions could be explained by enhancement of cerebrovascular function. We examined this possibility by measuring the effects of PDE5 and PDE4 inhibitor treatment on local cerebral blood flow and glucose utilization in rats using [ 14 C]-iodoantipyrine and [ 14 C]-2-deoxyglucose quantitative autoradiography, respectively. In the spatial location task, PDE5 inhibition (cGMP) with vardenafil enhanced only early phase consolidation, PDE4 inhibition (cAMP) with rolipram enhanced only late phase consolidation, and PDE2 inhibition (cAMP and cGMP) with Bay 60-7550 enhanced both consolidation processes. Furthermore, PDE5 inhibition had no cerebrovascular effects in hippocampal or rhinal areas. PDE4 inhibition increased rhinal, but not hippocampal blood flow, whereas it decreased glucose utilization in both areas. In general, PDE5 inhibition decreased the ratio between blood flow and glucose utilization, indicative of general oligaemia; whereas PDE4 inhibition increased this ratio, indicative of general hyperemia. Both oligaemic and hyperemic conditions are detrimental for brain function and do not explain memory enhancement. These results underscore the specific effects of cAMP and cGMP on memory consolidation (object and spatial memory) and provide evidence that the underlying mechanisms of PDE inhibition on cognition are independent of cerebrovascular effects.

show abstract

“…PDE4 inhibition by compounds that targeted the active site of the enzyme bestowed therapeutic advantages in animal models of chronic obstructive pulmonary disease (COPD) [69,70], rheumatoid arthritis [71], inflammatory bowel disease [72], and psoriasis [73]. PDE4 inhibitors have also been shown effective in promoting memory function [74], treating depression [75,76], protecting against some aspects of Alzheimer's disease [77], and reversing age-associated memory deficits [78]. There is also a growing body of evidence suggesting that PDE4 inhibition may also be effective for the treatment of certain cancers [79].…”

Section: Inhibition Of Pde4 As a Therapeutic Strategymentioning

confidence: 99%