Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance

Boess, Frank; Hendrix, Martin; Staay, Franz Josef van der; Erb, Christina; Schreiber, Rudy; Staveren, Wilma van; Vente, Jan de; Prickaerts, Jos; Blokland, Arjan; Koenig, Gerhard

doi:10.1016/j.neuropharm.2004.07.040

Cited by 300 publications

(283 citation statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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

Rutten

Donkelaar

Ferrington

et al. 2009

Neuropsychopharmacol

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112

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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.

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Section: Discussionmentioning

confidence: 99%

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

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112

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“…Thus, activity-dependent increases in cGMP levels appear to have a potent, inhibitory effect on the induction of LTP by some patterns of synaptic activity. Indeed, a recent study has found that selective inhibition of the cGMP-activated phosphodiesterase PDE2 enhances learning on a number of different behavioral tasks (Boess et al, 2004), suggesting that cGMP-activated phosphodiesterases have an important, inhibitory role in the neuronal mechanisms underlying memory formation. Our results reveal a molecular mechanism that could underlie this role of cGMP in memory formation and suggest that cross-talk between cAMP and cGMP signaling pathways mediated by cGMP-stimulated phosphodiesterases is a key, modulatory component of the network of postsynaptic signaling pathways regulating LTP induction.…”

Section: Discussionmentioning

confidence: 99%

A novel role for cyclic guanosine 3′,5′monophosphate signaling in synaptic plasticity: A selective suppressor of protein kinase A-dependent forms of long-term potentiation

et al. 2006

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At excitatory synapses onto hippocampal CA1 pyramidal cells, activation of cyclic AMP-dependent protein kinase and subsequent down-regulation of protein phosphatases has a crucial role in the induction of long-term potentiation by low-frequency patterns of synaptic stimulation. Because the second messenger cyclic guanosine 3′,5′monophosphate can regulate the activity of different forms of the cyclic AMP degrading enzyme phosphodiesterase, we examined whether increases in cyclic guanosine 3′,5′monophosphate can modulate long-term potentiation induction in the mouse hippocampal CA1 region through effects on cyclic AMP signaling. Using the cyclic guanosine 3′,5′ monophosphate-specific phosphodiesterase inhibitor zaprinast or the nitric oxide donor S-nitroso-D,L-penicillamine to elevate cyclic guanosine 3′,5′monophosphate levels we found that increases in cyclic guanosine 3′,5′monophosphate strongly inhibit the induction of long-term potentiation by lowfrequency patterns of synaptic stimulation where protein kinase A activation is required for longterm potentiation induction. In contrast, zaprinast and S-nitroso-D,L-penicillamine had no effect on the induction of long-term potentiation by high-frequency patterns of synaptic stimulation that induce long-term potentiation in a protein kinase A-independent manner. Directly activating protein kinase A with the phosphodiesterase-resistant cyclic AMP analog 8-Br-cAMP, blocking all phosphodiesterases with 3-isobutyl-1-methylxanthine, or inhibiting protein phosphatases rescued long-term potentiation induction in zaprinast-treated slices. Together, these results suggest that increases in cyclic guanosine 3′,5′monophosphate inhibit long-term potentiation by activating phosphodiesterases that interfere with the protein kinase A-mediated suppression of protein phosphatases needed for long-term potentiation induction. Consistent with the notion that this cyclic guanosine 3′,5′mono-phosphate-mediated inhibitory pathway is recruited by some patterns of synaptic activity, blocking cyclic guanosine 3′,5′monophosphate production strongly facilitated the induction of long-term potentiation by long trains of theta-frequency synaptic stimulation. Together, our results indicate that increases in cyclic guanosine 3′,5′monophosphate can act as a long-term potentiation suppressor mechanism that selectively constrains the induction of protein kinase A-*Corresponding author. Tel: +1-310-206-4654; fax: +1-310-206-5661. E-mail address: todell@mednet.ucla.edu (T. J. O'Dell).. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2007 March 26. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript dependent forms of long-term potentiation induced by low-frequency patterns of synaptic stimulation. Keywordshippocampus; cyclic nucleotides; phosphodiesterase; protein phosphataseThe cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway has a crucial role in learning in animals as diverse as Aplysia, Drosophila, and mammals (Bailey et al....

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“…The first specific inhibitor discovered for PDE2 is erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), but its use has been limited due to its inhibitory effects on adenosine deaminase even at low concentrations [250] . Four more PDE2 specific inhibitors, IC933 [247] , Bay 60-7550 [251] , (9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one (PDP) [252] , and oxindole [253] , have recently been described. Nevertheless, since the highly specific inhibitors of PDE1 and PDE2 are still relatively new in experimental studies and far from any clinical use targeting the heart, their potential impact on cardiac contractility cannot be adequately described at the present time.…”

Section: Regulatory Role Of Other Phosphodiesterases In the Heartmentioning

confidence: 99%

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Rao

2008

Acta Pharmacol Sin

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Phosphodiesterases (PDEs) are enzymes that degrade cellular cAMP and cGMP and are thus essential for regulating the cyclic nucleotides. At least 11 families of PDEs have been identified, each with a distinctive structure, activity, expression, and tissue distribution. The PDE type-3, -4, and -5 (PDE3, PDE4, PDE5) are localized to specific regions of the cardiomyocyte, such as the sarcoplasmic reticulum and Z-disc, where they are likely to influence cAMP/cGMP signaling to the end effectors of contractility. Several PDE inhibitors exhibit remarkable hemodynamic and inotropic properties that may be valuable to clinical practice. In particular, PDE3 inhibitors have potent cardiotonic effects that can be used for short-term inotropic support, especially in situations where adrenergic stimulation is insufficient. Most relevant to this review, PDE inhibitors have also been found to have cytoprotective effects in the heart. For example, PDE3 inhibitors have been shown to be cardioprotective when given before ischemic attack, whereas PDE5 inhibitors, which include three widely used erectile dysfunction drugs (sildenafil, vardenafil and tadalafil), can induce remarkable cardioprotection when administered either prior to ischemia or upon reperfusion. This article provides an overview of the current laboratory and clinical evidence, as well as the cellular mechanisms by which the inhibitors of PDE3, PDE4 and PDE5 exert their beneficial effects on normal and ischemic hearts. It seems that PDE inhibitors hold great promise as clinically applicable agents that can improve cardiac performance and cell survival under critical situations, such as ischemic heart attack, cardiopulmonary bypass surgery, and heart failure.

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Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance

Cited by 300 publications

References 71 publications

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

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

A novel role for cyclic guanosine 3′,5′monophosphate signaling in synaptic plasticity: A selective suppressor of protein kinase A-dependent forms of long-term potentiation

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

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