Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D

Sierksma, Annerieke; Hove, Daniël L.A. van den; Pfau, F.; Philippens, M.; Bruno, Olga; Fedele, Ernesto; Ricciarelli, Roberta; Steinbusch, H.W.M.; Vanmierlo, Tim; Prickaerts, Jos

doi:10.1016/j.neuropharm.2013.09.015

Cited by 116 publications

(91 citation statements)

References 59 publications

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“…This first compound Gebr-7b was effective in improving cognition in a mouse APP/PS1 model of AD, as was also found for the follow-up compound Gebr32a in Tg2576 mice [71]. Gebr-7b had no effect on hippocampal Aβ load [72]. The latter was also reported in previous studies with the classic PDE4 inhibitor rolipram, yet it rescued decreased CREB activation [73,74].…”

Section: Phosphodiesterasesupporting

confidence: 78%

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Prickaerts

Heckman

Blokland

2017

Expert Opinion on Investigational Drugs

144

168

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Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability. Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually. ARTICLE HISTORY

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Section: Phosphodiesterasesupporting

confidence: 78%

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Prickaerts

Heckman

Blokland

2017

Expert Opinion on Investigational Drugs

144

168

View full text Add to dashboard Cite

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“…Interestingly, we show that Syk inhibition results in a stimulation of CREB phosphorylation via PKA activation suggesting that Syk inhibition could also have neuroprotective properties because stimulation of CREB phosphorylation by PKA is known to confer neuroprotection (73)(74)(75). Also, PKA and CREB phosphorylation are down-regulated in AD brains (76) and in transgenic mouse models of AD overexpressing A␤, whereas stimulation of PKA/ CREB phosphorylation with various compounds improves memory in AD mouse models (77)(78)(79)(80) suggesting that Syk inhibition has the potential to reduce memory impairments by stimulating PKA/CREB signaling. We have summarized the Syk signaling events that regulate AD-related processes highlighting the potential therapeutic application of Syk inhibitors in AD (Fig.…”

Section: Discussionmentioning

confidence: 79%

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

Paris

Ait‐Ghezala

Bachmeier

et al. 2014

Journal of Biological Chemistry

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Background: Spleen tyrosine kinase (Syk) mediates microglial activation and neurotoxicity elicited by Alzheimer A␤ peptides. Results: Syk regulates A␤ production via NFB-dependent mechanisms and Tau phosphorylation by controlling the activation of glycogen synthase 3␤. Conclusion: Inhibition of Syk can interrupt the neuroinflammation, pathological A␤ accumulation, and Tau hyperphosphorylation in AD. Significance: Syk represents a therapeutic target for the key pathological lesions that define AD.

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“…1) increased memory performances in the object location test (OLT) and the object recognition test (ORT) in rodents, 13 and improved spatial memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease (AD). 20 Interestingly, 7b did not induce any emetic-like effect at doses 33-100 times higher than those effective on memory, as assessed with the taste reactivity test on rats and the xylazine/ketamine test on mice. 13 In 2010, Burgin et al reported a PDE4D allosteric modulator able to revert the scopolamine-induced cognitive impairment in the Y maze test and to improve memory performance in the ORT.…”

Section: Introductionmentioning

confidence: 90%

Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors

Brullo¹,

Massa²,

Villa³

et al. 2015

Bioorganic & Medicinal Chemistry

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Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D

Cited by 116 publications

References 59 publications

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors

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