Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats

Devan, Bryan D.; Sierra‐Mercado, Demetrio; Jimenez, Mariana; Bowker, Jonna L.; Duffy, Kara B.; Spangler, Edward L.; Ingram, Donald K.

doi:10.1016/j.pbb.2004.09.019

Cited by 86 publications

(51 citation statements)

References 44 publications

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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%

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

Rutten

Donkelaar

Ferrington

et al. 2009

Neuropsychopharmacol

113

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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%

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

Rutten

Donkelaar

Ferrington

et al. 2009

Neuropsychopharmacol

113

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“…Injection volume was ≤1 ml/kg body weight. Injection time and the dose of L-NAME were based on the pilot work described above, while the injection time and the doses of sildenafil were based on the positive results reported in our previous work (Devan et al 2004), with the exception of the 1.0-mg/kg dose included in the main experiment after obtaining a significant effect of the 1.5-mg/kg dose.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, we have recently shown that systemic administration of the phosphodiesterase type 5 (PDE5) inhibitor sildenafil citrate has cognitive-enhancing effects in attenuating the complex maze learning impairment induced by blockade of muscarinic cholinergic receptors (Devan et al 2004). Other studies also show that increasing cGMP through inhibition of PDE5, an enzyme that degrades cGMP via hydrolysis, improves cognition in animals (Baratti and Boccia 1999;Prickaerts et al 2004Prickaerts et al , 2005 and may have positive effects on attention and memory in humans (Schultheiss et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition

et al. 2005

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“…A recent study demonstrated that sildenafil improves spatial memory in the Morris Water Maze (MWM) test when administered after the last training trial on each day of the acquisition phase of the test. 84 In addition to its effects on hippocampal-dependent memory, sildenafil improves performance of a prefrontal-cortex-dependent cognition test in monkeys, 58 and attenuates memory impairment induced by nitric oxide synthase inhibition, 55,80 hyperammonemia, 81 blockade of muscarinic cholinergic receptors, 85 diabetes conditions, and electroconvulsive shock. 86 In addition to PDE5, PDE6 and PDE9 are specific for cGMP, with the latter exhibiting the greatest affinity for cGMP (K m = 170 nM), 87 highlighting its importance in the regulation of cGMP downstream signaling pathways.…”

Section: 54mentioning

confidence: 99%

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

García‐Osta¹,

Cuadrado‐Tejedor²,

García‐Barroso³

et al. 2012

ACS Chem. Neurosci.

233

179

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Alzheimer's disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action.

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Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats

Cited by 86 publications

References 44 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

Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

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