Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis.

@article{Robichaud2002DeletionOP,
  title={Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis.},
  author={A. Robichaud and P. Stamatiou and S. Jin and N. Lachance and D. Macdonald and F. Lalibert{\'e} and Susana Liu and Z. Huang and M. Conti and Chi-chung Chan},
  journal={The Journal of clinical investigation},
  year={2002},
  volume={110 7},
  pages={
          1045-52
        }
}
A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis in non-vomiting species. Among the family-specific PDE inhibitors, PDE4 inhibitors reduced the duration of xylazine/ketamine-induced anesthesia in mice, with no effect on pentobarbital-induced anesthesia. The rank order of the PDE4 inhibitors tested was… Expand
Luteolin, a non-selective competitive inhibitor of phosphodiesterases 1-5, displaced [3H]-rolipram from high-affinity rolipram binding sites and reversed xylazine/ketamine-induced anesthesia.
TLDR
Although luteolin non-selectively and competitively inhibited PDE1-5, only PDE4 inhibition contributed to a reversing effect, and the gastrointestinal adverse effects such as nausea, vomiting and gastric hypersecretion should be carefully monitored, because of the low therapeutic (PDE4(H)/PDE 4(L)) ratio. Expand
Antidepressant-like effects of the phosphodiesterase-4 inhibitor etazolate and phosphodiesterase-5 inhibitor sildenafil via cyclic AMP or cyclic GMP signaling in mice
TLDR
The results suggest that inhibition of PDE4 by etazolate or PDE5 by sildenafil produced antidepressant-like effects in CUMS-treated animals via cAMP or cGMP signaling, which shares the common downstream signal pathway of CREB/BDNF/VGF. Expand
The Identification of a Novel Phosphodiesterase 4 Inhibitor, 1-Ethyl-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,3,4-oxadiazol-2-yl}-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (EPPA-1), with Improved Therapeutic Index using Pica Feeding in Rats as a Measure of Emetogenicity
TLDR
In vitro and in vivo anti-inflammatory potencies of the first-generation PDE4 inhibitor, rolipram, the second-generation inhibitors, roflumilast and cilomilast, and a novel third generation inhibitor are determined and EPPA-1 is identified as a novel PDE 4 inhibitor with an improved therapeutic index. Expand
CHF6001 II: A Novel Phosphodiesterase 4 Inhibitor, Suitable for Topical Pulmonary Administration—In Vivo Preclinical Pharmacology Profile Defines a Potent Anti-Inflammatory Compound with a Wide Therapeutic Window
TLDR
CHF6001 was found effective and extremely well tolerated upon topical administration in relevant animal models, and may represent a step forward in PDE4 inhibition for the treatment of asthma and chronic obstructive respiratory disease. Expand
Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline
TLDR
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Antipsychotic profile of rolipram: efficacy in rats and reduced sensitivity in mice deficient in the phosphodiesterase-4B (PDE4B) enzyme
TLDR
Rolipram has a pharmacologic profile similar to that of the atypical antipsychotics and has low extrapyramidal symptom liability, suggesting that PDE4B mediates the antipsychotic effects of rolipram in CAR and that the PDE 4B-regulated cyclic adenosine monophosphate signaling pathway may play a role in the pathophysiology and pharmacotherapy of psychosis. Expand
Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme
RationalePhosphodiesterases (PDEs) belonging to the PDE4 family control intracellular concentrations of cyclic adenosine monophosphate (cAMP) by catalyzing its hydrolysis. Four separate PDE4 genesExpand
Phosphodiesterase-4D Knock-down in the Prefrontal Cortex Alleviates Chronic Unpredictable Stress-Induced Depressive-Like Behaviors and Memory Deficits in Mice
TLDR
Animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and camp-ERK1/2- CREB signaling and neuroplasticity, indicating a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE 4 inhibitors for depression and concomitant memory deficits. Expand
Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice
TLDR
An allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region, was 100-fold more potent for improving memory than in wild-type mice and exhibited low potency in a mouse surrogate model for emesis, and clinical potential for PDE 4D-selective inhibitors is suggested. Expand
Mice deficient in phosphodiesterase-4A display anxiogenic-like behavior
TLDR
These results suggest that PDE4A may be important in the regulation of emotional memory and anxiety-like behavior, but not emesis, and could possibly represent a novel therapeutic target in the future for anxiety or disorders affecting memory. Expand
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