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Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis
Open accessAbstract
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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Giembycz, M. A. (2006) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2006.02640.x · Cited by 68
Guo, J., Lin, P., Zhao, X., Zhang, J., Wei, X., Wang, Q., & Wang, C. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.01.008 · Cited by 72
“Unfortunately, the development of PDE4 inhibitor rolipram for therapeutic purposes has been hindered by side effects, such as emesis (Robichaud et al., 2001, 2002; Dyke and Montana, 2002).”
Phosphodiesterase Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease
Page, C. P. (2014) · International Archives of Allergy and Immunology · doi:10.1159/000368800 · Cited by 66
Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode
Kranz, M., Wall, M., Evans, B., Miah, A. H., Ballantine, S. P., Delves, C. J., Dombroski, B., Gross, J. W., Schneck, J. L., Villa, J. P., et al. (2009) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2009.03.061 · Cited by 66
Drug safety evaluation of roflumilast for the treatment of COPD: a meta-analysis
Rogliani, P., Calzetta, L., Cazzola, M., & Matera, M. G. (2016) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2016.1199683 · Cited by 66
Phosphodiesterase Inhibitors as Potential Cognition Enhancing Agents
Schmidt, C. J. (2010) · Current Topics in Medicinal Chemistry · doi:10.2174/156802610790411009 · Cited by 64
“Although emesis cannot be observed in rodents, studies using KO mice have suggested that the emetic activity of PDE4 inhibitors may be attributed to inhibition of PDE4D [54].”
BackgroundPreferential inhibition of human phosphodiesterase 4 by ibudilast
Huang, Z., Liu, S., Zhang, L., Salem, M., Greig, G. M., Chan, C., Natsumeda, Y., & Noguchi, K. (2005) · Life Sciences · doi:10.1016/j.lfs.2005.10.026 · Cited by 63
Self-citationRedondo, M., Brea, J. M., Pérez, D. I., Soteras, I., Val, C., Pérez, C., Morales-Garcia, J. A., Alonso‐Gil, S., Paúl-Fernández, N., Martin-Alvarez, R., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm201720d · Cited by 61
2 PDE4 Inhibitors – A Review of the Current Field
Press, N. J., & Banner, K. H. (2009) · Progress in medicinal chemistry · doi:10.1016/s0079-6468(08)00202-6 · Cited by 60
Mice deficient in phosphodiesterase-4A display anxiogenic-like behavior
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Self-citationFortin, M., Danjou, H., Higgins, M., Gougeon, J., Aubé, P., Moktefi, K., Mouissi, S., Séguin, S., Seguin, R. M., RENZI, P. M., et al. (2009) · Respiratory Research · doi:10.1186/1465-9921-10-39 · Cited by 59
“For example, as systemic PDE4D inhibition appears to be responsible for the emetic effect [33], PDE4B-specific inhibitors might provide better therapeutic ratios.”
BackgroundSelige, J., Hatzelmann, A., & Dunkern, T. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22529 · Cited by 56
“PDE4D seems also to be responsible for the known central nervous system-related and cardiac-related side effects of PDE4 selective inhibitors observed in mice (Robichaud et al., 2002; Lehnart et al., 2005).”
BackgroundGross, N. J., Giembycz, M. A., & Rennard, S. I. (2010) · COPD Journal of Chronic Obstructive Pulmonary Disease · doi:10.3109/15412551003758304 · Cited by 56
The cyclic AMP phenotype of fragile X and autism
Kelley, D. J., Bhattacharyya, A., Lahvis, G. P., YIN, J., Malter, J. S., & Davidson, R. J. (2008) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.06.005 · Cited by 60
Novel signal transduction modulators for the treatment of airway diseases
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Putting the lid on phosphodiesterase 4
Houslay, M. D., & Adams, D. R. (2010) · Nature Biotechnology · doi:10.1038/nbt0110-38 · Cited by 54
Kroegel, C., & Foerster, M. (2006) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.16.1.109 · Cited by 54
Villetti, G., Carnini, C., Battipaglia, L., Preynat, L., Bolzoni, P. T., Bassani, F., Caruso, P. L., Bergamaschi, M., Pisano, A. R., Puviani, V., et al. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.220558 · Cited by 52
“…site conformer of PDE4 over the high-affinity rolipram-binding conformer (Barnette et al., 1996; Rocque et al., 1997) or the isoform PDE4B over the isoform PDE4D (Robichaud et al., 2002b; Lehnart et al., 2005), but both these approaches have been only partially validated (Duplantier et al., 1996).”
BackgroundResultInfluentialWang, Z., Zhang, Y., Liu, Y., Zhao, N., Zhang, Y., Li, Y., An, L., Li, J., Wang, X., Qin, J., et al. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02225.x · Cited by 51
“Unfortunately, no PDE4 inhibitors to date have been approved for clinical utility for these therapeutic profiles due to the concomitant side effects, in particular emesis (Robichaud et al., 2001; Spina, 2008), which appears to be PDE4 isoform-specific (Robichaud et al., 2002b).”
BackgroundMethodInfluentialWang, Z., Yang, W., Zhang, Y., Zhao, N., Zhang, Y., Liu, Y., Xu, Y., Wilson, S. P., O’Donnell, J. M., Zhang, H., et al. (2015) · Scientific Reports · doi:10.1038/srep11332 · Cited by 52
Intracellular Targeting of Phosphodiesterase‐4 Underpins Compartmentalized cAMP Signaling
Lynch, M. J., Hill, E. V., & Houslay, M. D. (2006) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(06)75007-4 · Cited by 50
Reininger, D., Fundel‐Clemens, K., Mayr, C. H., Wollin, L., Laemmle, B., Quast, K., Nickolaus, P., & Herrmann, F. E. (2024) · British Journal of Pharmacology · doi:10.1111/bph.17303 · Cited by 48
“However, the full potential of these pan-PDE4 inhibitors (active against PDE4A, B, C and D) has been restricted by gastrointestinal adverse events (e.g., nausea, vomiting and diarrhoea), thought to be predominantly associated with the inhibition of the PDE4D isoenzyme (Robichaud et al., 2002).”
Punit K Srivastava, Dastidar, S. G., & Ray, A. (2007) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.16.7.1069 · Cited by 48
Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis
Abdulrahim, H., Thistleton, S., Adebajo, A., Shaw, T., Edwards, C. J., & Wells, A. F. (2015) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2015.1034107 · Cited by 47
“Apremilast does not have any marked PDE4 subtype selectivity, which may explain its improved therapeutic index and favorable side effect profile, for example emesis in cilomilast [73] and central nervous system effects in rolipram [59].”
BackgroundArmani, E., Amari, G., Rizzi, A., Fanti, R. D., Ghidini, E., Capaldi, C., Carzaniga, L., Caruso, P. L., Guala, M., Peretto, I., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401549m · Cited by 47
Imidazo[1,2-b]pyridazine as privileged scaffold in medicinal chemistry: An extensive review
Garrido, A., Vera, G., Delaye, P., & Enguehard‐Gueiffier, C. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113867 · Cited by 47
Selective phosphodiesterase-4 inhibitors in chronic obstructive lung disease
Soto, F. J., & Hanania, N. A. (2005) · Current Opinion in Internal Medicine · doi:10.1097/01.mcp.0000151715.58124.9e · Cited by 47
Metadata
- 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
- Venue
- Journal of Clinical Investigation
- Published
- 2002-10-01
- Volume
- 110
- Issue
- 7
- Pages
- 1045-1052
- ISSN
- 0021-9738 (ISSN-L)
- 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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