Acute treatment with the PDE4 inhibitor roflumilast improves verbal word memory in healthy old individuals: a double-blind placebo-controlled study

Blokland, Arjan; Duinen, Marlies A. van; Sambeth, Anke; Heckman, Pim R. A.; Tsai, Max; Lahu, Gëzim; Uz, Tolga; Prickaerts, Jos

doi:10.1016/j.neurobiolaging.2019.01.014

Cited by 50 publications

(51 citation statements)

References 36 publications

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“…Patients with stabilized schizophrenia receiving adjuvant roflumilast in a small Phase II trial showed no improvement in working memory but did show some improvement in verbal learning and memory (126). Given these positive findings, roflumilast was tested in elderly subjects who demonstrated no change in spatial memory but improved verbal word memory with roflumilast treatment (127). Numerous preclinical studies have long pointed to the therapeutic potential of PDE4i's in the context of schizophrenia and cognition (128)(129)(130)(131).…”

Section: Pde4 Inhibitorsmentioning

confidence: 99%

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

Baillie

Tejeda

Kelly

2019

Nat Rev Drug Discov

237

295

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Section: Pde4 Inhibitorsmentioning

confidence: 99%

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

Baillie

Tejeda

Kelly

2019

Nat Rev Drug Discov

237

295

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“…Cognitive enhancement in humans is scarcely achieved, however, it has been noted with the PDE4 inhibitor roflumilast in several preclinical trials, establishing proof of concept that PDE4 is a therapeutic target for AD [10,11]. The potential effects of these inhibitors are attributed to the widely recognized action of cAMP on memory formation [12,13] and cognition [10,11,14,15]. The mechanisms underpinning these functions relate to intracellular increases in cerebral cAMP that activate PKA associated with cAMP response element binding (CREB) protein.…”

Section: Pde4 Enzymes Orchestrate Signaling Via Crebmentioning

confidence: 99%

Understanding PDE4's function in Alzheimer's disease; a target for novel therapeutic approaches

Tibbo

Tejeda

Baillie

2019

Biochemical Society Transactions

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Phosphodiesterases (PDEs) have long been considered as targets for the treatment of Alzheimer's disease (AD) and a substantial body of evidence suggests that one sub-family from the super-family of PDEs, namely PDE4D, has particular significance in this context. This review discusses the role of PDE4 in the orchestration of cAMP response element binding signaling in AD and outlines the benefits of targeting PDE4D specifically. We examine the limited available literature that suggests PDE4 expression does not change in AD brains together with reports that show PDE4 inhibition as an effective treatment in this age-related neurodegenerative disease. Actually, aging induces changes in PDE4 expression/activity in an isoform and brain-region specific manner that proposes a similar complexity in AD brains. Therefore, a more detailed account of AD-related alterations in cellular/tissue location and the activation status of PDE4 is required before novel therapies can be developed to target cAMP signaling in this disease.

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“…The extract’s ability to inhibit MAO-B, an enzyme that metabolises dopamine, which itself plays a key role in working memory and executive function [ 56 , 57 ], is certainly a candidate as the primary mechanism here. The inhibition of the enzyme PDE4, which hydrolyses the cellular second messenger cyclic adenosine monophosphate (cAMP), might be expected to principally affect long-term memory [ 58 ], which was not measured in this study. However, the mechanisms of action of the various classes of phytochemicals typically found in Avena sativa extracts may also apply here.…”

Section: Discussionmentioning

confidence: 99%

Acute and Chronic Effects of Green Oat (Avena sativa) Extract on Cognitive Function and Mood during a Laboratory Stressor in Healthy Adults: A Randomised, Double-Blind, Placebo-Controlled Study in Healthy Humans

Kennedy

Bonnländer²,

Lang³

et al. 2020

Nutrients

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Green oat (Avena sativa) extracts contain several groups of potentially psychoactive phytochemicals. Previous research has demonstrated improvements in cognitive function following a single dose of these extracts, but not following chronic supplementation. Additionally, whilst green oat extracts contain phytochemicals that may improve mood or protect against stress, for instance species-specific triterpene saponins, to date this possibility has not been examined. The current study investigated the effects of a single dose and four weeks of administration of a novel, Avena sativa herbal extract (cognitaven®) on cognitive function and mood, and changes in psychological state during a laboratory stressor. The study adopted a dose-ranging, double-blind, randomised, parallel groups design in which 132 healthy males and females (35 to 65 years) received either 430 mg, 860 mg, 1290 mg green oat extract or placebo for 29 days. Assessments of cognitive function, mood and changes in psychological state during a laboratory stressor (Observed Multitasking Stressor) were undertaken pre-dose and at 2 h and 4 h post-dose on the first (Day 1) and last days (Day 29) of supplementation. The results showed that both a single dose of 1290 mg and, to a greater extent, supplementation for four weeks with both 430 mg and 1290 mg green oat extract resulted in significantly improved performance on a computerised version of the Corsi Blocks working memory task and a multitasking task (verbal serial subtractions and computerised tracking) in comparison to placebo. After four weeks, the highest dose also decreased the physiological response to the stressor in terms of electrodermal activity. There were no treatment-related effects on mood. These results confirm the acute cognitive effects of Avena sativa extracts and are the first to demonstrate that chronic supplementation can benefit cognitive function and modulate the physiological response to a stressor.

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Acute treatment with the PDE4 inhibitor roflumilast improves verbal word memory in healthy old individuals: a double-blind placebo-controlled study

Cited by 50 publications

References 36 publications

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

Understanding PDE4's function in Alzheimer's disease; a target for novel therapeutic approaches

Acute and Chronic Effects of Green Oat (Avena sativa) Extract on Cognitive Function and Mood during a Laboratory Stressor in Healthy Adults: A Randomised, Double-Blind, Placebo-Controlled Study in Healthy Humans

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