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

Devan, Bryan D.; Bowker, Jonna L.; Duffy, Kara B.; Bharati, Ila Sri; Jimenez, Mariana; Sierra‐Mercado, Demetrio; Nelson, Christopher M.; Spangler, Edward L.; Ingram, Donald K.

doi:10.1007/s00213-005-0232-z

Cited by 73 publications

(56 citation statements)

References 48 publications

(51 reference statements)

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“…However, there are a number of other potential mechanisms by which PDE5 inhibitors may have a positive influence on heart failure, and the impact of these effects is, as yet, unclear. Therefore, despite a variety of encouraging 22 Heart failure Aortic banding in mice, 16 only minor effects in pacing induced heat failure in dogs 28 Improvement in flow-mediated vasodilatation in CHF patients 26,27 Raynaud's disease None Significant reduction in frequency and duration of Raynaud attacks 33 Cognitive dysfunction PDE5 expression profiling, [36][37][38][39] in vitro studies, 36,42 behavioral models with rodents [43][44][45][46][47] None Stroke Various stroke models in rats 42,[50][51][52][53] None Female sexual dysfunction PDE5 expression and activity in vitro [58][59][60] ; isolated organ bath 61,62 Moderate effects in pre-and post-menopausal women, [63][64][65][66] 126,127 Abbreviations: BPS, benign prostate syndrome; CHF, congestive heart failure; LUTS, lower urinary tract symptoms; PAH, pulmonary hypertension; PDE5, phosphodiesterase type-5.…”

Section: Discussionmentioning

confidence: 99%

“…This hypothesis is supported by the finding that learning impairment in rats can be induced by administration of the NOsynthase inhibitor L-NAME which, in turn, can be attenuated by intraperitoneal administration of sildenafil. 46,47 The effects of PDE5 inhibitors on memory processes in humans have only been studied sporadically. So far, no clear effects on behavioral measures of attention and verbal recognition memory have been reported.…”

Section: Pde5 Inhibitors To Treat Central Nervous System Disordersmentioning

confidence: 99%

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PDE5 inhibitors beyond erectile dysfunction

et al. 2007

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The phosphodiesterase type-5 (PDE5) inhibitors sildenafil, vardenafil and tadalafil are widely used first-line therapy for erectile dysfunction (ED). Since the advent of sildenafil in 1998, more than 40 million men worldwide have been successfully treated with these compounds. The safety and high tolerability of PDE5 inhibitors make them an attractive tool to investigate further physiological functions of PDE5, for example the modulation of intracellular cyclic GMP (cGMP) pools. As cGMP is a key component of intracellular signaling this may provide novel therapeutic opportunities beyond ED even for indications in which chronic administration is necessary. The approval of sildenafil for the treatment of pulmonary hypertension in 2005 was a notable success in this area of research. A number of other potential new indications are currently in various phases of preclinical research and development. In recent years, extensive but very heterogeneous information has been published in this field. The aim of this review is to summarize existing preclinical and clinical knowledge and critically discuss the evidence to support potential future indications for PDE5 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Pde5 Inhibitors To Treat Central Nervous System Disordersmentioning

confidence: 99%

PDE5 inhibitors beyond erectile dysfunction

et al. 2007

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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.

218

176

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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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“…92 Sildenafil also attenuates learning impairment induced by blockade of cholinergic muscarinic receptors in rats by modulating NO-cGMP signal transduction, a pathway implicated in age-related cognitive decline and neurodegenerative disease. 93 Therefore, in addition to promoting neuroregeneration after stroke treatment, sildenafil may also enhance cognitive function, and can be used to treat cholinergic dysfunction in age-related cognitive decline and Alzheimer's dementia (AD).…”

Section: Pde-5 Inhibitors Cgmp and No Donorsmentioning

confidence: 99%

Neurorestorative treatment of stroke: Cell and pharmacological approaches

Chen

Chopp

2006

NeuroRX

153

114

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Summary:There is a compelling need to develop cell and pharmacological therapeutic approaches to be administered beyond the hyperacute phase of stroke. These therapies capitalize on the capacity of the brain for neuroregeneration and neuroplasticity and are designed to reduce neurological deficits after stroke. This review provides an update of bone marrowderived mesenchymal stem cells (MSCs) and select pharmacological agents in clinical use for other indications that promote the recovery process in the subacute and chronic phases after stroke. Among these agents are 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors (statins), erythropoietin (EPO), and phosphodiesterase type 5 (PDE-5) inhibitors and nitric oxide (NO) donors. Both the MSCs and the pharmacologic agents potentiate brain plasticity and neurobehavioral recovery after stroke.

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

Abstract: The results indicate that sildenafil may improve learning by modulating NO-cGMP signal transduction, a pathway implicated in age-related cognitive decline and neurodegenerative disease.

Cited by 73 publications

References 48 publications

PDE5 inhibitors beyond erectile dysfunction

PDE5 inhibitors beyond erectile dysfunction

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

Neurorestorative treatment of stroke: Cell and pharmacological approaches

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