Phosphodiesterase 4D: an enzyme to remember

Ricciarelli, Roberta; Fedele, Ernesto

doi:10.1111/bph.13257

Cited by 23 publications

(21 citation statements)

References 62 publications

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“…D159687, that do not completely inhibit enzymatic activity (Imax ~ 80-90%) [10,34]. Another approach is to design selective full (Imax 100%) PDE4D inhibitors, such as Gebr7b, that nevertheless show a partial reduction in emetic potential [35] (and recently reviewed in [36]). Because of the reduced emetic properties of roflumilast in humans we explored in the present preclinical study whether roflumilast has the potential to test as a translational cognition enhancer (e.g.…”

Section: Introductionmentioning

confidence: 99%

The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses

Vanmierlo

Creemers

Akkerman

et al. 2016

Behavioural Brain Research

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Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.

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Section: Introductionmentioning

confidence: 99%

The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses

Vanmierlo

Creemers

Akkerman

et al. 2016

Behavioural Brain Research

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“…PDE4D5 has been found to selectively interact with Rheb in HEK293 cells ( 35 – 37 ). We confirmed the interaction of these two proteins in primary white adipocytes by coimmunoprecipitation experiments ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway

et al. 2017

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Beiging of white adipose tissue has potential antiobesity and antidiabetes effects, yet the underlying signaling mechanisms remain to be fully elucidated. Here we show that adipose-specific knockout of Rheb, an upstream activator of mechanistic target of rapamycin complex 1 (mTORC1), protects mice from high-fat diet–induced obesity and insulin resistance. On the one hand, Rheb deficiency in adipose tissue reduced mTORC1 signaling, increased lipolysis, and promoted beiging and energy expenditure. On the other hand, overexpression of Rheb in primary adipocytes significantly inhibited CREB phosphorylation and uncoupling protein 1 (UCP1) expression. Mechanistically, fat-specific knockout of Rheb increased cAMP levels, cAMP-dependent protein kinase (PKA) activity, and UCP1 expression in subcutaneous white adipose tissue. Interestingly, treating primary adipocytes with rapamycin only partially alleviated the suppressing effect of Rheb on UCP1 expression, suggesting the presence of a novel mechanism underlying the inhibitory effect of Rheb on thermogenic gene expression. Consistent with this notion, overexpression of Rheb stabilizes the expression of cAMP-specific phosphodiesterase 4D5 (PDE4D5) in adipocytes, whereas knockout of Rheb greatly reduced cellular levels of PDE4D5 concurrently with increased cAMP levels, PKA activation, and UCP1 expression. Taken together, our findings reveal Rheb as an important negative regulator of beige fat development and thermogenesis. In addition, Rheb is able to suppress the beiging effect through an mTORC1-independent mechanism.

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“…Presumably, these processes occur gradually over many years in the preclinical phase of AD and then continue during its clinical progression (Calsolaro and Edison, 2016). Second, a vast number of investigations have demonstrated that boosting long-term potentiation (LTP) by blocking PDE4D represents the molecular trigger to improve memory formation and consolidation (Ricciarelli and Fedele, 2015). As LTP is considered a correlate of learning and memory, many findings have suggested that age-related changes in the LTP level may also impact cognitive functions during aging (Rose et al, 2005;Villeda et al, 2011;Ricciarelli et al, 2017).…”

Section: Pde4d and Cognitive Dysfunction In Alzheimer's Diseasementioning

confidence: 99%

Phosphodiesterase 4D Gene Modifies the Functional Network of Patients With Mild Cognitive Impairment and Alzheimer’s Disease

et al. 2020

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is affected by several genetic variants. It has been demonstrated that genetic variants affect brain organization and function. In this study, using whole genome-wide association studies (GWAS), we analyzed the functional magnetic resonance imaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative dataset (ADNI) dataset and identified genetic variants associated with the topology of the functional brain network http://www. adni-info.org. We found three novel loci (rs2409627, rs9647533, and rs11955845) in an intron of the phosphodiesterase 4D (PDE4D) gene that contribute to abnormalities in the topological organization of the functional network. In particular, compared to the wildtype genotype, the subjects carrying the PDE4D variants had altered network properties, including a significantly reduced clustering coefficient, small-worldness, global and local efficiency, a significantly enhanced path length and a normalized path length. In addition, we found that all global brain network attributes were affected by PDE4D variants to different extents as the disease progressed. Additionally, brain regions with alterations in nodal efficiency due to the variations in PDE4D were predominant in the limbic lobe, temporal lobe and frontal lobes. PDE4D has a great effect on memory consolidation and cognition through long-term potentiation (LTP) effects and/or the promotion of inflammatory effects. PDE4D variants might be a main reasons underlyling for the abnormal topological properties and cognitive impairment. Furthermore, we speculated that PDE4D is a risk factor for neural degenerative diseases and provided important clues for the earlier detection and therapeutic intervention for AD.

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Phosphodiesterase 4D: an enzyme to remember

Cited by 23 publications

References 62 publications

The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses

The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses

Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway

Phosphodiesterase 4D Gene Modifies the Functional Network of Patients With Mild Cognitive Impairment and Alzheimer’s Disease

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