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Graß, Hildegard; Klotz, Theodor; Fathian-Sabet, B.; Berghaus, Günter; Engelmann, U.; Käferstein, H

doi:10.1023/a:1017573722074

Cited by 39 publications

(14 citation statements)

References 7 publications

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“…However, based on our previous data with PDE inhibitors in SOL animals, we assume that EE animals are insensitive to vardenafil treatment. This lack of effect of vardenafil on memory in EE rats resembles the ineffectiveness of this drug on human memory performance [54]–[56] and suggests that, compared to SOL/SOC animals, the EE rat could be considered as a more valid animal model for testing cognition enhancing drugs [3], [4].…”

Section: Discussionmentioning

confidence: 99%

PDE5 Inhibition Improves Object Memory in Standard Housed Rats but Not in Rats Housed in an Enriched Environment: Implications for Memory Models?

et al. 2014

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Drug effects are usually evaluated in animals housed under maximally standardized conditions. However, it is assumed that an enriched environment (EE) more closely resembles human conditions as compared to maximally standardized laboratory conditions. In the present study, we examined the acute cognition enhancing effects of vardenafil, a PDE5 inhibitor, which stimulates protein kinase G/CREB signaling in cells, in three different groups of male Wistar rats tested in an object recognition task (ORT). Rats were either housed solitarily (SOL) or socially (SOC) under standard conditions, or socially in an EE. Although EE animals remembered object information longer in the vehicle condition, vardenafil only improved object memory in SOL and SOC animals. While EE animals had a heavier dorsal hippocampus, we found no differences between experimental groups in total cell numbers in the dentate gyrus, CA2–3 or CA1. Neither were there any differences in markers for pre- and postsynaptic density. No changes in PDE5 mRNA- and protein expression levels were observed. Basal pCREB levels were increased in EE rats only, whereas β-catenin was not affected, suggesting specific activation of the MAP kinase signaling pathway and not the AKT pathway. A possible explanation for the inefficacy of vardenafil could be that CREB signaling is already optimally stimulated in the hippocampus of EE rats. Since previous data has shown that acute PDE5 inhibition does not improve memory performance in humans, the use of EE animals could be considered as a more valid model for testing cognition enhancing drugs.

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Section: Discussionmentioning

confidence: 99%

PDE5 Inhibition Improves Object Memory in Standard Housed Rats but Not in Rats Housed in an Enriched Environment: Implications for Memory Models?

et al. 2014

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“…82 In another study of six healthy participants sildenafil enhanced performance in a simple reaction time test, but not on other measures (including short term memory and divided attention). 83…”

Section: Discussionmentioning

confidence: 99%

“…Whether the cognitive effects observed in the two single-dose studies in healthy individuals 82,83 can be sustained with longer-term administration is unclear. However, the case reports of single subjects with disease states (spastic quadriplegia and stroke) reported improvements in symptoms lasting seven 85 to over 12 months 84 in motor and visual symptoms, respectively.…”

Section: Discussionmentioning

confidence: 99%

The effect of phosphodiesterase-5 inhibitors on cerebral blood flow in humans: A systematic review

Pauls

Moynihan

Barrick

et al. 2017

J Cereb Blood Flow Metab

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Agents that augment cerebral blood flow (CBF) could be potential treatments for vascular cognitive impairment. Phosphodiesterase-5 inhibitors are vasodilating drugs established in the treatment of erectile dysfunction (ED) and pulmonary hypertension. We reviewed published data on the effects of phosphodiesterase-5 inhibitors on CBF in adult humans. A systematic review according to PRISMA guidelines was performed. Embase, Medline and Cochrane Library Trials databases were searched. Sixteen studies with 353 participants in total were retrieved. Studies included healthy volunteers and patients with migraine, ED, type 2 diabetes, stroke, pulmonary hypertension, Becker muscular dystrophy and subarachnoid haemorrhage. Most studies used middle cerebral artery flow velocity to estimate CBF. Few studies employed direct measurements of tissue perfusion. Resting CBF velocity was unaffected by phosphodiesterase-5 inhibitors, but cerebrovascular regulation was improved in ED, pulmonary hypertension, diabetes, Becker's and a group of healthy volunteers. This evidence suggests that phosphodiesterase-5 inhibitors improve responsiveness of the cerebral vasculature, particularly in disease states associated with an impaired endothelial dilatory response. This supports the potential therapeutic use of phosphodiesterase-5 inhibitors in vascular cognitive impairment where CBF is reduced. Further studies with better resolution of deep CBF are warranted. The review is registered on the PROSPERO database (registration number CRD42016029668).

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“…Although the literature is limited, there is evidence that chronic PDE5 inhibition may be neurologically beneficial. For example, although a single dose of sildenafil does not cause a clear improvement in cognition in healthy adults [ 36 ], chronic administration of udenafil has been shown to lead to an improvement in both general cognitive function as well as frontal executive function [ 37 ]. This has led some to suggest that in humans, the therapeutic benefits of PDE5 inhibition may be best seen after chronic inhibition rather than after a single dose [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease

Teich

Sakurai

Patel

et al. 2016

JAD

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Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue. We then show that PDE5 protein exists in human brain by western blot and ELISA. Most importantly, we performed immunohistochemistry and demonstrate that PDE5 is present in human neurons. We hope that this work will trigger a renewed interest in the development of PDE5 inhibitors for neurologic disease.

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Cited by 39 publications

References 7 publications

PDE5 Inhibition Improves Object Memory in Standard Housed Rats but Not in Rats Housed in an Enriched Environment: Implications for Memory Models?

PDE5 Inhibition Improves Object Memory in Standard Housed Rats but Not in Rats Housed in an Enriched Environment: Implications for Memory Models?

The effect of phosphodiesterase-5 inhibitors on cerebral blood flow in humans: A systematic review

PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease

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