The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D

Mori, Fumiaki; Pérez-Torres, S.; De, Raffaele; Porzionato, Andrea; Macchi, Veronica; Beleta, Jörge; Gavaldà, Amadeu; Palacios, J.M.; Mengod, Guadalupe

doi:10.1016/j.jchemneu.2010.03.004

Cited by 79 publications

(60 citation statements)

References 68 publications

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“…The complex pattern of splice isoforms allows subtypes of PDE4 to be targeted to different cellular microdomains and for isoform-and subtypeselective regulation of PDE4 activity by accessory proteins [27]. PDE4A, B, and D are expressed in brain [28][29][30][31][32].…”

Section: Subtype-selective Pde4 Inhibitors Provide Opportunities For mentioning

confidence: 99%

Phosphodiesterase-4 (PDE4) Molecular Pharmacology and Alzheimer's Disease

2015

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Between 20% and 25% of patients diagnosed with Alzheimer's disease (AD) do not have amyloid burden as assessed by positron emission tomography imaging. Thus, there is a need for nonamyloid-directed therapies for AD, especially for those patients with non-amyloid AD. The family of phosphodiesterase-4 (PDE4) enzymes are underexploited therapeutic targets for central nervous system indications. While the PDE4A, B, and D subtypes are expressed in brain, the strict amino acid sequence conservation of the active site across the four subtypes of PDE4 has made it difficult to discover subtype inhibitors. The recent elucidation of the structure of the PDE4 N-and C-terminal regulatory domains now makes it possible to design subtype-selective, negative allosteric modulators (PDE4-NAMs). These act through closing the N-terminal UCR2 or C-terminal CR3 regulatory domains, and thereby inhibit the enzyme by blocking access of cyclic adenosine monophosphate (cAMP) to the active site. PDE4B-NAMs have the potential to reduce neuroinflammation by dampening microglia cytokine production triggered by brain amyloid, while PDE4D-NAMs have potent cognitive benefit by augmenting signaling through the cAMP/protein kinase A/ cAMP response element-binding protein (CREB) pathway for memory consolidation. The importance of PDE4D for human cognition is underscored by the recent discovery of PDE4D mutations in acrodysostosis (ACRDY2: MIM 600129), an ultra rare disorder associated with intellectual disability. Thus, the family of PDE4 enzymes provides rich opportunities for the development of mechanistically novel drugs to treat neuroinflammation or the cognitive deficits in AD.

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Section: Subtype-selective Pde4 Inhibitors Provide Opportunities For mentioning

confidence: 99%

Phosphodiesterase-4 (PDE4) Molecular Pharmacology and Alzheimer's Disease

2015

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“…Thus, emesis and nausea are clearly class effects of PDE4 inhibitors. They are likely due to inhibition of PDE4 in brain regions responsible for the emetic reflex, such as the area postrema and nucleus of the solitary tract in which PDE4 is highly expressed [73-75] as well as PDE4 inhibition in the gut, and remain the main obstacles for PDE4 inhibitor development today.…”

Section: The Pde4 Family As a Target For Cognition Enhancementmentioning

confidence: 99%

PDE4 as a target for cognition enhancement

Richter

Menniti

Zhang

et al. 2013

Expert Opinion on Therapeutic Targets

124

105

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Introduction The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs. Areas covered PDE4 is the largest of the eleven mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation. Expert opinion PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors.

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“…73 Furthermore, use of phosphodiesterase inhibitors (such as rolipram) increase cAMP tissue levels, which consequently causes excessive nausea and vomiting in both vomit competent animals and humans. 74 We have also demonstrated that increased PKA-phosphorylation is associated with peak vomit frequency during both immediate and delayed phases of vomiting caused by either cisplatin or cyclophosphamide in the least shrew. We have established the post-receptor emetic signaling pathway for selective 5-HT 3 R agonist 2-Me-5-HT in the least shrew.…”

Section: + -Related Signaling Pathway In Emesis Camp-pkamentioning

confidence: 62%

Role of Calcium in Vomiting: Revelations from the Least Shrew Model of Emesis

Darmani

Zhong²

2015

Gastro Open J

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Citation-ATPase inhibitor) cause vomiting in the least shrew, whereas blockade of LTCC by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic activity against diverse emetogens including agonists of 5-HT 3 (e.g. 5-HT or 2-Me-5-HT)-, NK 1 (GR73632)-, D 2 (apomorphine or quinpirole)-, and M 1 (McN-A343)-receptors, but can also potentiate the antiemetic efficacy of well-established antiemetic palonosetron against the non-specific emetogen, cisplatin. The transmission of emesis signals in the gastrointestinal tract and brainstem is crucially dependent on Ca 2+ channels in neurons. In this review, we will examine the current knowledge on the role of Ca 2+ channels and Ca 2+-dependent signaling pathways in the perception and modulation of emesis.

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The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D

Cited by 79 publications

References 68 publications

Phosphodiesterase-4 (PDE4) Molecular Pharmacology and Alzheimer's Disease

Phosphodiesterase-4 (PDE4) Molecular Pharmacology and Alzheimer's Disease

PDE4 as a target for cognition enhancement

Role of Calcium in Vomiting: Revelations from the Least Shrew Model of Emesis

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