Cited by 267Phosphodiesterase function and regulationPharmacogenetics and Drug MetabolismVeterinary Pharmacology and Anesthesia

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Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

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Robichaud, Annette, Stamatiou, Panagiota B., Jin, S.-L.Catherine, Lachance, Nicholas, MacDonald, Dwight, Laliberté, France, Liu, Susana, Huang, Zheng, Conti, Marco, Chan, Chi-Chung·2002·Journal of Clinical Investigation

DOI 10.1172/jci15506PMC PMC151147

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Abstract

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 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (PMNPQ) > (R)-rolipram > (S)-rolipram >> (R)-N-[4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl]N'-ethylurea (CT-2450). The specific roles of PDE4B and PDE4D in this model were studied using mice deficient in either subtype. PDE4D-deficient mice, but not PDE4B-deficient mice, had a shorter sleeping time than their wild-type littermates under xylazine/ketamine-induced anesthesia, but not under that induced with pentobarbital. Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice compared with their wild-type littermates. While PMNPQ significantly reduced the xylazine/ketamine-induced anesthesia period in wild-type mice and in PDE4B-null mice, it had no effect in PDE4D-deficient mice. These findings strongly support the hypothesis that inhibition of PDE4D is pivotal to the anesthesia-reversing effect of PMNPQ and is likely responsible for emesis induced by PDE4 inhibitors.

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“…(e.g. area postrema and nucleus of the solitary tract; Cherry and Davis., 1999; Lamontagne et al., 2001; Mori et al., 2010) and its deletion in transgenicmice reduced the xylazine/ketamine-induced anaesthesia, a test used to measure emetic potential in nonvomiting species (Robichaud et al., 2002).”
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Phosphodiesterase-4 Inhibition in Parkinson’s Disease: Molecular Insights and Therapeutic Potential
Roy, D., Balasubramanian, S., Krishnamurthy, P. T., Sola, P., & Rymbai, E. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01349-1 · Cited by 24
“The results showed that PDE4D inhibition was most likely responsible for emetogenic and other adverse effects (Robichaud et al. 2002).”
Background
Ablation of specific long PDE4D isoforms increases neurite elongation and conveys protection against amyloid-β pathology
Paes, D., Schepers, M., Willems, E., Rombaut, B., Tiane, A., Solomina, Y., Tibbo, A. J., Blair, C. M., Kyurkchieva, E., Baillie, G. S., et al. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04804-w · Cited by 26
“The molecular mechanisms underlying these side effects remain to be defined but seem to be induced by PDE4(D) inhibition in both the emetic brainstem regions as well as the gastrointestinal system [13, 24, 92].”
Background
Evaluation of the Therapeutic Index of a Novel Phosphodiesterase 4B–Selective Inhibitor Over Phosphodiesterase 4D in Mice
Suzuki, O., Mizukami, K., Etori, M., Sogawa, Y., Takagi, N., Tsuchida, H., Morimoto, K., Goto, T., Yoshino, T., Mikkaichi, T., et al. (2013) · Journal of Pharmacological Sciences · doi:10.1254/jphs.13103fp · Cited by 24
Validation of the xylazine/ketamine anesthesia test as a predictor of the emetic potential of pharmacological compounds in rats
Nelissen, E., van Goethem, N. P., Bonassoli, V. T., Heckman, P. R. A., van Hagen, B. T. J., Suay, D., Wouters, C., & Prickaerts, J. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.01.026 · Cited by 24
Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury
Tang, H., Lu, J., Tang, J.-F., Zheng, X., Liang, Y., Wang, X., Wang, Y., Mao, L., & Chen, J. (2010) · International Immunopharmacology · doi:10.1016/j.intimp.2010.01.003 · Cited by 24
“The mechanism of the emetic response associated with PDE4 inhibitors is thought to be a consequence of the inhibition of PDE4D subtype [9,10], But which PDE4D subtype was involved in the nausea action was unclear.”
BackgroundMethod
Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension
Xing, Y., Hou, Y., Fan, T., Gao, R., Feng, X., Li, B., Pang, J., Guo, W., Shu, T., Li, J., et al. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.01.012 · Cited by 25
“Also, Pde4d KO mice are resistant to xylazine/ketamine-induced anesthesia, a behavior correlated with emesis in rodents 42 .”
Background
Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies
Nunes, I. K. D. C., de Souza, É. T., Martins, I. R. R., Barbosa, G., de Moraes, M. O., Medeiros, M. D. M., Silva, S. W. D., Balliano, T. L., da Silva, B. A., Silva, P., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112492 · Cited by 23
Small-molecule inhibitors of PDE-IV and -VII in the treatment of respiratory diseases and chronic inflammation
Vijayakrishnan, L., Rudra, S., Eapen, M. S., Dastidar, S. G., & Ray, A. (2007) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.16.10.1585 · Cited by 23
In vivo and in vitro measurement of brain phosphodiesterase 4 in rats after antidepressant administration
Fujita, M., Imaizumi, M., D'Sa, C. M., Zoghbi, S. S., Crescenzo, M. S., Hong, J. S., Musachio, J. L., Gee, A. D., Seidel, J., Green, M. V., et al. (2006) · Synapse · doi:10.1002/syn.20347 · Cited by 23
“Although to our knowledge, no study reported influence of isoflurane anesthesia on PDE4, one mouse study showed interactions between xylazine/ketamine anesthesia and PDE4 (Robichaud et al., 2002).”
Background
Pharmacophore generation and atom based 3D-QSAR of quinoline derivatives as selective phosphodiesterase 4B inhibitors
Sharma, V., Kumar, H., & Wakode, S. R. (2016) · RSC Advances · doi:10.1039/c6ra11210b · Cited by 23
A new model of Pde4d deficiency: genetic knock‐down of PDE4D enzyme in rats produces an antidepressant phenotype without spatial cognitive effects
Schaefer, T. L., Braun, A. A., Amos‐Kroohs, R. M., Williams, M. T., Ostertag, E. M., & Vorhees, C. V. (2012) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2012.00796.x · Cited by 22
“As mentioned, one study in Pde4d−/− mice showed no changes in 1-h contextual or cued fear conditioning, but showed impaired conditioning at 24 h in both contextual and cued fear (Rutten et al. 2008).”
Background
Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis
Ohba, F., Nomoto, M., Hojo, S., & Akama, H. (2015) · Journal of Dermatological Treatment · doi:10.3109/09546634.2015.1093587 · Cited by 22
“PDE4 inhibitors are thought to produce a pharmacological response analogous to that of presynaptic a2-adrenoceptor inhibitors by elevating intracellular levels of cAMP in noradrenergic neurons (18).”
Background
The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors
Aspiotis, R., Deschênes, D., Dubé, D., Girard, Y., Huang, Z., Laliberté, F., Liu, S., Papp, R., Nicholson, D. W., & Young, R. N. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.07.076 · Cited by 22
Self-citation
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
Davis, T. G., Peterson, J. J., Kou, J.-P., Capper-Spudich, E. A., Ball, D. I., Nials, A. T., Wiseman, J. O., Solanke, Y. E., Lucas, F. S., Williamson, R. A., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.152454 · Cited by 21
“Using a panel of PDE4 inhibitors, Robichaud et al. (1999, 2002) demonstrated previously that reduction of xylazine/ketamine-induced anesthesia in the mouse positively correlates with induction of vomiting in an emetic species, the ferret.”
Background
Synthesis and molecular docking of new roflumilast analogues as preferential-selective potent PDE-4B inhibitors with improved pharmacokinetic profile
Moussa, B. A., El‐Zaher, A. A., El-Ashrey, M. K., & Fouad, M. A. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.02.038 · Cited by 20
New insights into PDE4B inhibitor selectivity: CoMFA analyses and molecular docking studies
Guariento, S., Bruno, O., Fossa, P., & Cichero, E. (2015) · Molecular Diversity · doi:10.1007/s11030-015-9631-1 · Cited by 20
“Originally, knockout mice experiments and data obtained from several PDE4D inhibitors seemed to support the hypothesis that PDE4D inhibition is responsible of the aforementioned side effects [33,34].”
Background
Uterus‐relaxing effect of β2‐agonists in combination with phosphodiesterase inhibitors: Studies on pregnant ratin vivoand on pregnant human myometriumin vitro
Verli, J., Klukovits, A., Kormányos, Z., Hajagos‐Tóth, J., Ducza, E., Seres, A. B., Falkay, G., & Gáspár, R. (2012) · Journal of obstetrics and gynaecology research · doi:10.1111/j.1447-0756.2012.01929.x · Cited by 20
Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer’s Disease
Bales, K. R., Plath, N., Svenstrup, N., & Menniti, F. S. (2010) · Topics in medicinal chemistry · doi:10.1007/7355_2010_8 · Cited by 22
“have put forward the hypothesis that PDE4D is specifically involved in the emetic response [104].”
Background
CGH2466, a combined adenosine receptor antagonist, p38 mitogen‐activated protein kinase and phosphodiesterase type 4 inhibitor with potent in vitro and in vivo anti‐inflammatory activities
Trifilieff, A., Keller, T. H., Press, N. J., Howe, T. J., Gedeck, P., Beer, D., & Walker, C. (2005) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706132 · Cited by 20
“It has indeed been suggested that PDE4D inhibition is likely to be responsible for emesis (Robichaud et al., 2002).”
Background
Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD)
Press, N. J., Taylor, R., Fullerton, J. D., TRANTER, P. R., McCarthy, C., Keller, T. H., Arnold, N., Beer, D., Brown, L., Cheung, R., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00902 · Cited by 20
Phosphodiesterase 10A inhibitors as a novel therapeutic approach for schizophrenia
Siuciak, J. A., & Strick, C. A. (2007) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2.7.1001 · Cited by 19
Phosphodiesterase (PDE) inhibitor torbafylline (HWA 448) attenuates burn-induced rat skeletal muscle proteolysis through the PDE4/cAMP/EPAC/PI3K/Akt pathway
Joshi, R., Kadeer, N., Sheriff, S., Friend, L. A., James, J. H., & Balasubramaniam, A. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.06.012 · Cited by 19
“Recent knock-out studies have shown that emesis associated with PDE4 inhibitors is due to the selective inhibition of PDE4D subtype (Robichaud et al., 2002).”
Structure-based design of selective phosphodiesterase 4B inhibitors based on ginger phenolic compounds
Xing, M., Akowuah, G. A., Gautam, V., & Gaurav, A. (2016) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2016.1234417 · Cited by 19
“The side effects are proven to be associated with PDE4D inhibition as PDE4D is expressed in area postrema that is responsible for emetic response (Bamette et al., 1996; Robichaud et al., 2002).”
Background
Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline
Bureau, Y., Handa, M., Zhu, Y., Laliberté, F., Moore, C. S., Liu, S., Huang, Z., Macdonald, D., Xu, D., & Robertson, G. S. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.06.018 · Cited by 19
Self-citation
Evaluation of PDE4 inhibition for COPD
Wang, D., & Cui, X. (2006) · International Journal of COPD · doi:10.2147/copd.2006.1.4.373 · Cited by 19
“…Robichaud et al 2002), several researchers in the fi eld proposed to develop isoform-specifi c PDE4 inhibitors that reduce or completely avoid disturbing PDE4D activity and therefore do not trigger the emetic responses in the nervous system (Giembycz 2002; Robichaud et al 2002; Card et al 2004).”
Synthesis of pyrrolo[2,3-d]pyridazinones as potent, subtype selective PDE4 inhibitors
Giovannoni, M. P., Cesari, N., Graziano, A., Vergelli, C., Biancalani, C., Biagini, P., & Piaz, V. D. (2007) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756360601114700 · Cited by 19
“Moreover some authors suggested that PDE4D is the subtype responsible for the emetic side-effects[29].”
Background
The cAMP-phosphodiesterase 4 (PDE4) controls β-adrenoceptor- and CFTR-dependent saliva secretion in mice
Boyd, A., Aragon, I. V., Saleh, L. A., Southers, D., & Richter, W. (2021) · Biochemical Journal · doi:10.1042/bcj20210212 · Cited by 17
Hesperetin, a Selective Phosphodiesterase 4 Inhibitor, Effectively Suppresses Ovalbumin-Induced Airway Hyperresponsiveness without Influencing Xylazine/Ketamine-Induced Anesthesia
Shih, C.-H., Lin, L.-H., Hsu, H.-T., Wang, K.-H., Lai, C.-Y., Chen, C., & Ko, W. (2012) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2012/472897 · Cited by 17
Phosphodiesterase-4B as a Therapeutic Target for Cognitive Impairment and Obesity-Related Metabolic Diseases
Clapcote, S. J. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-58811-7_5 · Cited by 18
Aging-related hyperinflammation in endotoxemia is mediated by the α2A-adrenoceptor and CD14/TLR4 pathways
Leong, J., Zhou, M., Jacob, A., & Wang, P. (2010) · Life Sciences · doi:10.1016/j.lfs.2010.03.009 · Cited by 17
“Inhibition of the PDE4 enzyme has been shown to correlate with decreased TNFα release from LPS-stimulated whole blood, a cellular marker of nonselective PDE4 inhibition (Muise et al. 2002; Robichaud et al. 2002).”
Background
Rolipram, a specific type‐4 phosphodiesterase inhibitor, inhibits cyclophosphamide‐induced haemorrhagic cystitis in rats
Sakura, M., Masuda, H., Matsuoka, Y., Yokoyama, M., Kawakami, S., & Kihara, K. (2008) · British Journal of Urology · doi:10.1111/j.1464-410x.2008.07948.x · Cited by 17
A view into the catalytic pocket of cyclic nucleotide phosphodiesterases
Conti, M. (2004) · Nature Structural & Molecular Biology · doi:10.1038/nsmb0904-809 · Cited by 16
Self-citation
Identification and molecular characterization of a novel PDE4D11 cAMP-specific phosphodiesterase isoform
Lynex, C. N., Li, Z., Chen, M. L., Toh, K. Y., Low, R. W. C., Goh, D. L. M., & Tay, S. K. H. (2008) · Cellular Signalling · doi:10.1016/j.cellsig.2008.08.020 · Cited by 16
Insights into the Physiological Functions of PDE4 from Knockout Mice
Jin, S.-L. C., Richter, W., & Conti, M. (2006) · CRC Press eBooks · doi:10.1201/9781420020847.secc · Cited by 15
Self-citation
Diastereoselective synthesis and profiling of bicyclic imidazolidinone derivatives bearing a difluoromethylated catechol unit as potent phosphodiesterase 4 inhibitors
Dorokhov, V. S., Golovanov, I. S., Tartakovsky, V. A., Sukhorukov, A. Y., & Ioffe, S. L. (2018) · Organic & Biomolecular Chemistry · doi:10.1039/c8ob01039k · Cited by 15
Discovery of a novel orally active PDE-4 inhibitor effective in an ovalbumin-induced asthma murine model
Kwak, H. J., Nam, J. Y., Song, J. S., No, Z., Yang, S. D., & Cheon, H. G. (2012) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.04.016 · Cited by 14
Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior
Bolger, G. B., Smoot, L. H. M., & van Groen, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165704 · Cited by 14
Suppressive effects of rutin, quercitrin, and isoquercitrin on atypical allergic asthma in an animal model
Chen, L., & Ko, W. (2021) · Medicine in Drug Discovery · doi:10.1016/j.medidd.2021.100106 · Cited by 14
New Drug Therapies for COPD
Ross, C. L., & Hansel, T. T. (2013) · Clinics in Chest Medicine · doi:10.1016/j.ccm.2013.10.003 · Cited by 14
Synthesis, Pharmacological Profile and Docking Studies of New Sulfonamides Designed as Phosphodiesterase-4 Inhibitors
Nunes, I. K. D. C., de Souza, É. T., Cardozo, S. V. S., Carvalho, V. F., Romeiro, N. C., Silva, P., Martins, M. A., Barreiro, E. J., & Lima, L. M. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162895 · Cited by 14
S‐Petasin, the Main Sesquiterpene ofPetasites formosanus,Inhibits Phosphodiesterase Activity and Suppresses Ovalbumin‐Induced Airway Hyperresponsiveness
Shih, C., Huang, T.-J., Chen, C., Lin, Y., & Ko, W. (2009) · Evidence-based Complementary and Alternative Medicine · doi:10.1093/ecam/nep088 · Cited by 14
“[35] and modified by us, S-petasin (10–100 μmol/kg, s.”
Background
Phosphodiesterase 4D, cAMP specific
Houslay, M. D., & Conti, M. (2010) · AfCS-Nature Molecule Pages · doi:10.1038/mp.a000106.01 · Cited by 13
Self-citation
New drugs and targets for asthma and COPD
Hansel, T. T., & Barnes, P. J. (2010) · Progress in respiratory research/Progress in research in emphysema and chronic bronchitis/Progress in respiration research · doi:10.1159/000320793 · Cited by 13
Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach
Świerczek, A., Pociecha, K., Ślusarczyk, M., Chłoń‐Rzepa, G., Baś, S., Młynarski, J., Więckowski, K., Zadrożna, M., Nowak, B., & Wyska, E. (2020) · Pharmaceutical Research · doi:10.1007/s11095-019-2727-z · Cited by 13

Authors: Robichaud, A., Stamatiou, P. B., Jin, S.-L. C., Lachance, N., MacDonald, D., Laliberté, F., Liu, S., Huang, Z., Conti, M., & Chan, C.-C.
Affiliations: Merck Canada Inc. (Canada) (CA)
Stanford Medicine (US)
Corresponding author: Robichaud, Annette
ORCID: MacDonald, Dwight
Huang, Zheng
Conti, Marco
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2002-10-01
Volume: 110
Issue: 7
Pages: 1045-1052
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci15506
PMC: PMC151147
OpenAlex: W2170451911
Cited by: 267
References: 44
Citations by year: 2026: 4 · 2024: 5 · 2023: 6 · 2022: 3 · 2021: 11 · 2020: 10 · 2019: 8 · 2018: 7 · 2017: 14 · 2016: 10 · 2015: 11 · 2014: 22 · 2013: 11 · 2012: 19
FWCI: 3.83
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Child Health and Human Development
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD020788, HD20788)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Veterinary › Small Animals › Veterinary Pharmacology and Anesthesia
Keywords: PDE4D, PDE4B, phosphodiesterase-4 inhibitors, vomiting, ketamine-xylazine anesthesia, rolipram, sleep duration, cAMP signaling
MeSH terms: Anesthesia, Animals, Male, Mice, Inbred C57BL, Pentobarbital, Phosphodiesterase Inhibitors, Time Factors, Vomiting, 3',5'-Cyclic-AMP Phosphodiesterases, Receptors, Adrenergic, alpha-2, Mice, Cyclic Nucleotide Phosphodiesterases, Type 4

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Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

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