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1. In vitro and in vivo pharmacological characterization of ethyl-4-[trans-4-[((2S)-2-hydroxy-3-[4-hydroxy-3[(methylsulfonyl)amino]-phenoxy]propyl) amino]cyclohexyl]benzoate hydrochloride (SAR150640), a new potent and selective human beta3-adrenoceptor agonist for the treatment of preterm labor

Author

Croci, Tiziano, Cecchi, Roberto, Marini, Pietro, Rouget, Céline, Viviani, Nunzia, Germain, Guy, Guagnini, Fabio, Fradin, Yvon, Descamps, Laurence, Pascal, Marc, Advenier, Charles, Breuiller-Fouché, Michelle, Leroy, Marie-Josèphe, Bardou, Marc, Exploratory Research Department, Sanofi-Aventis, Biologie du développement et reproduction (BDR), Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Drug Safety Evaluation, Pharmacocinétique et Métabolisme Préclinique, Pharmacologie, Université Paris Descartes - Paris 5 (UPD5)-EA220, La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus (UMR_S 767), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Pharmacologie et Toxicologie, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biologie du développement et reproduction ( BDR ), Institut National de la Recherche Agronomique ( INRA ) -Ecole Nationale Vétérinaire d'Alfort-Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ) -EA220, La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus ( UMR_S 767 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physiopathologie et de Pharmacologie Cardiovasculaire Expérimentale (LPPCE), Université de Bourgogne (UB), Leroy, Marie Josèphe, École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH : Cell Line, MESH : Tocolytic Agents, MESH : Receptors, Adrenergic, beta-3, MESH : Adrenergic beta-Agonists, MESH: Sulfonamides, MESH : Isoproterenol, MESH: Adrenergic beta-Agonists, Oxytocin, Benzoates, MESH: Isoproterenol, Obstetric Labor, Propanolamines, Uterine Contraction, Vasotocin, MESH: Pregnancy, Competitive, Pregnancy, Receptors, Cyclic AMP, MESH : Female, MESH: Animals, MESH : Albuterol, MESH: Obstetric Labor, Premature, [ SDV.MHEP.GEO ] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Cells, Cultured, MESH: Cyclic AMP, Sulfonamides, Tumor, Cultured, Molecular Structure, MESH : Myometrium, MESH : Cyclic AMP, MESH : Obstetric Labor, Premature, MESH : Guanosine 5'-O-(3-Thiotriphosphate), MESH: Adrenergic beta-Antagonists, MESH: Vasotocin, Adrenergic beta-Agonists, Tocolytic Agents, MESH : Macaca fascicularis, Adrenergic, MESH: Guanosine 5'-O-(3-Thiotriphosphate), MESH: Uterine Contraction, Myometrium, MESH: Myometrium, Female, MESH : Transfection, MESH: Cells, Cultured, MESH : Benzoates, MESH: Cell Line, Tumor, MESH : Oxytocin, Cells, MESH : Adrenergic beta-Antagonists, Adrenergic beta-Antagonists, MESH: Molecular Structure, beta-3, Adrenergic beta-3 Receptor Agonists, MESH: Binding, Competitive, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Transfection, Binding, Competitive, Cell Line, Obstetric Labor, Premature, Cell Line, Tumor, MESH : Cells, Cultured, MESH: Oxytocin, Animals, Humans, Albuterol, MESH : Sulfonamides, MESH : Vasotocin, Premature, MESH: Propanolamines, MESH: Humans, MESH : Cell Line, Tumor, MESH : Binding, Competitive, MESH: Albuterol, MESH: Transfection, MESH : Humans, Isoproterenol, MESH : Propanolamines, Binding, MESH: Benzoates, MESH: Cell Line, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, MESH : Pregnancy, Macaca fascicularis, MESH: Macaca fascicularis, Guanosine 5'-O-(3-Thiotriphosphate), Receptors, Adrenergic, beta-3, MESH : Animals, MESH: Receptors, Adrenergic, beta-3, MESH: Female, MESH : Molecular Structure, MESH : Uterine Contraction, MESH: Tocolytic Agents
Abstract

International audience; Ethyl-4-[trans-4-[((2S)-2-hydroxy-3-[4-hydroxy-3[(methylsulfonyl)amino] phenoxy]propyl) amino]cyclohexyl]benzoate hydrochloride (SAR150640) was characterized as a new potent and selective beta(3)-adrenoceptor agonist for the treatment of preterm labor. SAR150640 and its major metabolite, the corresponding acid 4-[trans-4-[((2S)-2-hydroxy-3-[4-hydroxy-3[(methylsulfonyl) amino] phenoxy]propyl)amino]cyclohexyl]benzoic acid (SSR500400), showed high affinity for beta(3)-adrenoceptors (K(i) = 73 and 358 nM) and greater potency than (-)-isoproterenol in increasing cAMP production in membrane preparations from human neuroblastoma cells (SKNMC), which express native beta(3)-adrenoceptors (pEC(50) = 6.5, 6.2, and 5.1, respectively). SAR150640 and SSR500400 also increased cAMP production in membrane preparations from human uterine smooth muscle cells (UtSMC), which also express native beta(3)-adrenoceptors (pEC(50) = 7.7 and 7.7, respectively). In these cells, SAR150640 dose-dependently inhibited oxytocin-induced intracellular Ca(2+) mobilization and extracellular signal-regulated kinase 1/2 phosphorylation. SAR150640 and SSR500400 had no beta(1)- or beta(2)-agonist or antagonist activity in guinea pig atrium and trachea, or in human isolated atrium and bronchus preparations. Both compounds concentration-dependently inhibited spontaneous contractions in human near-term myometrial strips, with greater potency than salbutamol and 4-[3-[(1,1-dimethylethyl)-amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP12177) (pIC(50) = 6.4, 6.8, 5.9, and 5.8, respectively), but with similar potency to (-)-isoproterenol and atosiban (oxytocin/vasopressin V(1)a receptor antagonist). SAR150640 also inhibited the contractions induced by oxytocin and prostaglandin F(2alpha). In vivo, after intravenous administration, SAR150640 (1 and 6 mg/kg), but not atosiban (6 mg/kg), dose-dependently inhibited myometrial contractions in conscious unrestrained female cynomolgus monkeys, with no significant effects on heart rate or blood pressure. In contrast, salbutamol (50 and 250 microg/kg) had no inhibitory effect on uterine contractions, but it dose-dependently increased heart rate. These findings indicate a potential for the therapeutic use of SAR150640 in mammals during preterm labor.

Published
2007
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2. Cellular localization of apelin and its receptor in the anterior pituitary: evidence for a direct stimulatory action of apelin on ACTH release

Author

Marie-Thérèse Bluet-Pajot, Rodrigo Alvear-Perez, Philippe Zizzari, Catherine Llorens-Cortes, Annabelle Réaux-Le Goazigo, Jacques Epelbaum, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Llorens Cortes, Catherine

Subjects
Male, Pituitary gland, Endocrinology, Diabetes and Metabolism, MESH: Amino Acid Sequence, MESH: Receptors, G-Protein-Coupled, MESH: Base Sequence, MESH : Tissue Distribution, Receptors, G-Protein-Coupled, Rats, Sprague-Dawley, 0302 clinical medicine, MESH: Cricetulus, MESH: Pituitary Gland, MESH: Ligands, MESH : CHO Cells, Tissue Distribution, MESH: Animals, MESH: Peptide Fragments, MESH : Ligands, 0303 health sciences, MESH : Amino Acid Sequence, MESH : Cyclic AMP, MESH: Pituitary Gland, Anterior, MESH : Cricetinae, MESH : Protein Binding, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Apelin, MESH : Adrenocorticotropic Hormone, Intercellular Signaling Peptides and Proteins, MESH : Carrier Proteins, medicine.medical_specialty, endocrine system, MESH : Cell Membrane, MESH : Cricetulus, MESH: Carrier Proteins, Adrenocorticotropic hormone, 03 medical and health sciences, Adrenocorticotropic Hormone, Anterior pituitary, Pituitary Gland, Anterior, MESH: CHO Cells, Physiology (medical), MESH: Protein Binding, MESH: Tissue Distribution, MESH: Adrenocorticotropic Hormone, MESH: Humans, MESH: Molecular Sequence Data, MESH : Humans, Peptide Fragments, Endocrinology, Carrier Proteins, 030217 neurology & neurosurgery, MESH : Molecular Sequence Data, Physiology, MESH: Corticotrophs, MESH: Cricetinae, MESH : Models, Biological, MESH: Rats, Sprague-Dawley, Rats, Inbred WKY, MESH : Pituitary Gland, Receptor, Corticotrophs, Cellular localization, MESH: Cyclic AMP, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Apelin Receptors, MESH : Rats, MESH : Forskolin, medicine.anatomical_structure, MESH: Pituitary Hormones, Anterior, MESH: Calcium, MESH : Receptors, G-Protein-Coupled, MESH : Transfection, MESH: Forskolin, hormones, hormone substitutes, and hormone antagonists, MESH: Rats, Inbred WKY, Endocrine gland, MESH: Rats, MESH : Male, MESH : Rats, Inbred WKY, Biology, Models, Biological, MESH : Pituitary Hormones, Anterior, MESH : Pituitary Gland, Anterior, Pituitary Hormones, Anterior, Internal medicine, medicine, Animals, MESH : Calcium, 030304 developmental biology, Apelin receptor, MESH: Transfection, MESH : Peptide Fragments, MESH: Models, Biological, MESH : Corticotrophs, MESH : Rats, Sprague-Dawley, MESH: Male, Rats, MESH : Peptide Hormones, MESH: Peptide Hormones, MESH : Base Sequence, MESH : Animals, MESH: Cell Membrane
Abstract

Apelin is a bioactive peptide recently identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ. The presence of apelin-immunoreactive nerve fibers, together with the detection of apelin receptor mRNA in the parvocellular part of the paraventricular nucleus and the stimulatory action of apelin on corticotropin-releasing hormone release, indicate that apelin modulates adrenocorticotropin (ACTH) release via an indirect action on the hypothalamus. However, a direct action of apelin in the anterior pituitary cannot be excluded. Here, we provided evidence for the existence of an apelinergic system within the adult male rat pituitary gland. Double immunofluorescence staining indicated that apelin is highly coexpressed in the anterior pituitary, mainly in corticotrophs (96.5 ± 0.3%) and to a much lower extent in somatotropes (3.2 ± 0.2%). Using in situ hybridization combined with immunohistochemistry, a high expression of apelin receptor mRNA was also found in corticotrophs, suggesting a local interaction between apelin and ACTH. In an ex vivo perifusion system of anterior pituitaries, apelin 17 (K17F, 10−6M) significantly increased basal ACTH release by 41%, whereas apelin 10 (R10F, 10−6M), an inactive apelin fragment, was ineffective. In addition, K17F but not R10F induced a dose-dependent increase in K+-evoked ACTH release, with maximal increase being observed for a 10−6M concentration. Taken together, these data outline the potential role of apelin as an autocrine/paracrine-acting peptide on ACTH release and provide morphological and neuroendocrine basis for further studies that explore the physiological role of apelin in the regulation of anterior pituitary functions.

Published
2007
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3. Evidence for a role of phosphodiesterase 4 in lipopolysaccharide-stimulated prostaglandin E2 production and matrix metalloproteinase-9 activity in human amniochorionic membranes

Author

Céline Méhats, Stéphanie Oger, Emmanuelle Dallot, Marie-Josèphe Leroy, Dominique Cabrol, Développement humain : Croissance et différenciation, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Leroy, Marie Josèphe, Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM) - Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP) - Centre National de la Recherche Scientifique (CNRS) - Institut de Recherche pour le Développement (IRD) - Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP) - Centre National de la Recherche Scientifique (CNRS) - Institut de Recherche pour le Développement (IRD) - Université Paris Descartes - Paris 5 (UPD5) - Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH : Phosphodiesterase Inhibitors, medicine.medical_treatment, MESH: Adjuvants, Immunologic, Matrix metalloproteinase, MESH : Tissue Culture Techniques, MESH: Enzyme Precursors, MESH : Immune Sera, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, MESH: Up-Regulation, MESH: Immune Sera, MESH : Up-Regulation, 0303 health sciences, 030219 obstetrics & reproductive medicine, MESH : Cyclic AMP, MESH: Dinoprostone, Phosphodiesterase, Chorion, Up-Regulation, 3. Good health, Cell biology, MESH: Membrane Proteins, medicine.medical_specialty, MESH: Enzyme Activation, MESH : Cyclooxygenase 2, Immunology, MESH: Prostaglandin-Endoperoxide Synthases, MESH: Chorion, Dinoprostone, Proinflammatory cytokine, 03 medical and health sciences, Adjuvants, Immunologic, MESH : 3',5'-Cyclic-Nucleotide Phosphodiesterase, Humans, Amnion, MESH: Humans, Tumor Necrosis Factor-alpha, Immune Sera, MESH : Humans, Cilomilast, MESH: Matrix Metalloproteinase 9, Enzyme Activation, MESH : Pregnancy, Endocrinology, MESH : Rolipram, chemistry, MESH : Membrane Proteins, 3',5'-Cyclic-AMP Phosphodiesterases, MESH: Tumor Necrosis Factor-alpha, MESH: Lipopolysaccharides, MESH: Female, Lipopolysaccharides, MESH: Interleukin-10, Lipopolysaccharide, Phosphodiesterase Inhibitors, MESH : Lipopolysaccharides, MESH: Phosphodiesterase Inhibitors, Tissue Culture Techniques, chemistry.chemical_compound, MESH: Rolipram, Cyclic AMP, Immunology and Allergy, MESH : Female, MESH : Matrix Metalloproteinase 9, Prostaglandin E2, MESH: Cyclic AMP, MESH : Tumor Necrosis Factor-alpha, Enzyme Precursors, MESH : Prostaglandin-Endoperoxide Synthases, MESH : Enzyme Precursors, Interleukin-10, Cytokine, Matrix Metalloproteinase 9, MESH : Amnion, Female, MESH: Cyclooxygenase 2, Rolipram, medicine.drug, MESH : Dinoprostone, MESH: 3',5'-Cyclic-Nucleotide Phosphodiesterase, Biology, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, MESH : Interleukin-10, Internal medicine, medicine, MESH: Tissue Culture Techniques, MESH: Amnion, 030304 developmental biology, Membrane Proteins, Cyclic Nucleotide Phosphodiesterases, Type 4, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, MESH : Chorion, Cyclooxygenase 2, Prostaglandin-Endoperoxide Synthases, MESH : Adjuvants, Immunologic, MESH : Enzyme Activation
Abstract

Chorioamniotic infection is a leading cause of preterm premature rupture of fetal membranes (amnion and chorion). Bacterial infection induces an inflammatory response characterized by elevated production of proinflammatory cytokines; the latter activate the production of both PGs that stimulate uterine contractions, and matrix metalloproteinases (MMPs) that degrade the extracellular matrix of the chorioamniotic membranes. The inflammatory response is under the control of cAMP content, which is partly regulated by phosphodiesterases (PDE). In this study, we investigated the role of the PDE4 family in the inflammatory process triggered by LPS in a model of amniochorionic explants. We found that PDE4 family is the major cAMP-PDE expressed in human fetal membranes and that PDE4 activity is increased by LPS treatment. Selective inhibition of PDE4 activity affected LPS signaling, because PDE4 inhibitors (rolipram and/or cilomilast) reduced the release of the proinflammatory cytokine TNF-α and increased the release of the anti-inflammatory cytokine IL-10. PDE4 inhibition reduced cyclooxygenase-2 protein expression and PGE2 production and also modulated MMP-9, a key mediator of the membrane rupture process, by inhibiting pro-MMP-9 mRNA expression and pro-MMP-9 activity. These results demonstrate that the PDE4 family participates in the regulation of the inflammatory response associated with fetal membrane rupture during infection. The PDE4 family may be an appropriate pharmacological target for the management of infection-induced preterm delivery.

Published
2005

4. Platelet-activating factor does not stimulate cAMP formation from immature forms of freshly isolated leukaemic blasts

Author

Yves Denizot, Magali Donnard, Jean Faucher, Pascal Turlure, Dominique Bordessoule, Véronique Truffinet, Franck Trimoreau, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations ( PMRIL ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Centre National de la Recherche Scientifique ( CNRS ), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Cancer Research, CD34, PAF receptor, chemistry.chemical_compound, Cyclic AMP, MESH : Precursor Cell Lymphoblastic Leukemia-Lymphoma, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, CAMP formation, MESH: Cyclic AMP, MESH: Middle Aged, blast cells, MESH : Cyclic AMP, Cell Differentiation, Hematology, respiratory system, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Cell biology, Haematopoiesis, Leukemia, Myeloid, Acute, Oncology, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), Female, MESH: Leukemia, Myeloid, Acute, MESH : Cell Differentiation, Intracellular, MESH: Cell Differentiation, MESH: Cell Line, Tumor, NLM, MESH : Male, MESH : Leukemia, Myeloid, Acute, Phospholipid, Biology, Mediator, Precursor cell, Cell Line, Tumor, Humans, MESH : Middle Aged, Platelet Activating Factor, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Platelet Activating Factor, MESH: Humans, Platelet-activating factor, MESH : Cell Line, Tumor, MESH : Humans, MESH: Male, chemistry, MESH : Platelet Activating Factor, MESH: Female
Abstract

To the Editor,PAF is a phospholipid mediator that sparks off awide range of immunoregulatory actions on maturehaematopoietic cells [1]. Intracellular and nuclearPAF-receptors (PAF-R) are reported [2–5]. Theybelong to the G-protein-coupled family. Studieshighlight the presence of PAF-R transcripts innormal haematopoietic CD34

Published
2005
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5. Anti-inflammatory and utero-relaxant effects in human myometrium of new generation phosphodiesterase 4 inhibitors

Author

Mary S. Barnette, Céline Méhats, Stéphanie Oger, Françoise Ferré, Marie-Josèphe Leroy, Dominique Cabrol, Reproduction et physiopathologie obstétricale: Déterminisme hormonal et mécanismes moléculaires de la parturition, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, Service de Gynécologie et Obstétrique [Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mehats, Celine, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP]

Subjects
Lipopolysaccharides, Cyclohexanecarboxylic Acids, Hydrocarbons, Fluorinated, MESH : Hydrocarbons, Fluorinated, MESH : Phosphodiesterase Inhibitors, MESH : Bronchodilator Agents, Phosphodiesterase Inhibitors, Anti-Inflammatory Agents, Carboxylic Acids, MESH : Cyclic Nucleotide Phosphodiesterases, Type 3, MESH : Lipopolysaccharides, MESH : Cyclic Nucleotide Phosphodiesterases, Type 4, MESH: Phosphodiesterase Inhibitors, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Uterine Contraction, chemistry.chemical_compound, 0302 clinical medicine, PDE4B, MESH: Pregnancy, Pregnancy, MESH: Rolipram, Cyclic AMP, MESH : Nitriles, MESH : Female, MESH: Cyclic AMP, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, 030219 obstetrics & reproductive medicine, Forskolin, MESH : Myometrium, MESH : Cyclic AMP, Myometrium, Phosphodiesterase, General Medicine, MESH: Nitriles, Bronchodilator Agents, 3. Good health, MESH : Carboxylic Acids, MESH: Carboxylic Acids, In utero, MESH: 3',5'-Cyclic-AMP Phosphodiesterases, MESH: Uterine Contraction, MESH: Myometrium, Female, MESH: Cyclic Nucleotide Phosphodiesterases, Type 3, Rolipram, Ethers, medicine.drug, MESH: Cyclic Nucleotide Phosphodiesterases, Type 4, MESH : 3',5'-Cyclic-AMP Phosphodiesterases, medicine.medical_specialty, In Vitro Techniques, MESH : Anti-Inflammatory Agents, Biology, 03 medical and health sciences, Internal medicine, Nitriles, medicine, Humans, Potency, MESH : Ethers, 030304 developmental biology, MESH: Humans, Tumor Necrosis Factor-alpha, MESH : Humans, Cilomilast, Cell Biology, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Cyclic Nucleotide Phosphodiesterases, Type 3, Cyclic Nucleotide Phosphodiesterases, Type 4, MESH: Hydrocarbons, Fluorinated, MESH : Pregnancy, Endocrinology, MESH : Rolipram, Reproductive Medicine, chemistry, 3',5'-Cyclic-AMP Phosphodiesterases, MESH: Anti-Inflammatory Agents, MESH: Tumor Necrosis Factor-alpha, MESH: Ethers, MESH: Bronchodilator Agents, MESH: Lipopolysaccharides, MESH: Female, MESH : Uterine Contraction
Abstract

International audience; The anti-inflammatory and utero-relaxant effects of two potent phosphodiesterase 4 (PDE4) inhibitors of the latest generation: cilomilast (one of the most advanced PDE4 inhibitors in clinical development, reportedly more selective for PDE4D) and compound A (which displays 12-fold greater selectivity toward PDE4B and/or PDE4A than toward PDE4D) were evaluated in human uterine smooth muscle. We first established that these compounds exhibit greater efficacy in inhibiting total cAMP-PDE activity in pregnant versus nonpregnant myometrium (E(max) = 78.0% +/- 3.6% and 80.3% +/- 2.2% in pregnant versus 57% +/- 4.7% and 70.5% +/- 5.9% in nonpregnant women for compound A and cilomilast, respectively; P < 0.05 for both compounds), confirming the prominent participation of PDE4 isoforms in cAMP hydrolysis in the near-term pregnant myometrium. Using pregnant myometrial explants, we have shown that both these drugs and also rolipram, the prototype PDE4 inhibitor, produce concentration-dependent inhibition of lipopolysaccharide (LPS) induced tumor necrosis factor alpha (TNFalpha) release with similar potency in each case (pD2 = 8.0 +/- 0.5, 7.9 +/- 0.2, and 7.6 +/- 0.2 for compound A, cilomilast, and rolipram, respectively). The maximum inhibition produced is 65%. Pretreatment with forskolin or 8-bromo-cAMP mimics the PDE4 inhibitor effect. Furthermore, compound A and cilomilast both produce concentration-dependent inhibition of the spontaneous contractions of myometrial strips and are more potent in pregnant than in nonpregnant myometrium (pD2 = 7.3 +/- 0.7 and 8.1 +/- 0.3 in pregnant versus 6.2 +/- 0.9 and 6.6 +/- 0.1 in nonpregnant myometrium for compound A and cilomilast, respectively; P < 0.05 for both compounds). This demonstrates that the PDE4 isoforms involved in the mechanism of contraction are different in the pregnant and nonpregnant myometrium. Our study highlights the importance of developing PDE4 inhibitors for the pharmacological management of infection-induced preterm labor.

Published
2004
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6. Alternative splicing of the dopamine D2 receptor directs specificity of coupling to G-proteins

Author

Jean-Pierre Montmayeur, Jocelyn Ceraline, Janique Guiramand, Madhav Bhatia, Emiliana Borrelli, Neurobiologie de l'audition-plasticité synaptique, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Altération génétique des cancers, chimioprévention et réponse thérapeutique, University of California [Irvine] (UC Irvine), University of California (UC), Guiramand, Janique, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] ( IBMM ), Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), University of California [Irvine] ( UCI ), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), University of California [Irvine] (UCI), and University of California

Subjects
MESH : Receptors, Dopamine D2, Apomorphine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mutant, MESH : Alternative Splicing, MESH: Amino Acid Sequence, MESH: Base Sequence, Biochemistry, Insert (molecular biology), Adenylyl cyclase, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, MESH: Animals, MESH: Dopamine Agonists, MESH : GTP-Binding Proteins, 0303 health sciences, MESH : Amino Acid Sequence, MESH : Cyclic AMP, MESH: Alternative Splicing, Spiperone, MESH: Spiperone, Adenylate Cyclase, MESH : Cloning, Molecular, MESH : Dopamine, G protein, Molecular Sequence Data, beta-2, Transfection, 03 medical and health sciences, MESH : Dopamine Agonists, Dopamine D2, MESH: Adenylate Cyclase, Humans, MESH: Cloning, Molecular, Amino Acid Sequence, Molecular Biology, MESH : Mutagenesis, Insertional, MESH: Humans, MESH: Molecular Sequence Data, Receptors, Dopamine D2, MESH : Humans, Isoproterenol, Molecular, MESH: Cell Line, Mutagenesis, Insertional, Alternative Splicing, chemistry, MESH: Receptors, Adrenergic, beta-2, 030217 neurology & neurosurgery, Cloning, MESH : Cell Line, MESH : Molecular Sequence Data, Dopamine, MESH : Receptors, Adrenergic, beta-2, MESH : Isoproterenol, MESH: Apomorphine, MESH : Adenylate Cyclase, MESH: Isoproterenol, chemistry.chemical_compound, MESH: Receptors, Dopamine D2, Receptors, Cyclic AMP, Cloning, Molecular, Receptor, MESH: Cyclic AMP, MESH: Kinetics, Recombinant Proteins, MESH : Spiperone, MESH : Apomorphine, Adrenergic, Dopamine Agonists, MESH : Kinetics, MESH : Transfection, MESH: GTP-Binding Proteins, MESH : Recombinant Proteins, MESH: Dopamine, Biology, Cell Line, GTP-binding protein regulators, GTP-Binding Proteins, Dopamine receptor D2, Insertional, MESH : Mice, Animals, MESH: Mice, 030304 developmental biology, Base Sequence, MESH: Transfection, Alternative splicing, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell Biology, Kinetics, MESH: Mutagenesis, Insertional, Mutagenesis, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Adenylyl Cyclase Inhibitors, MESH : Base Sequence, Receptors, Adrenergic, beta-2, MESH : Animals
Abstract

International audience; Two isoforms of the dopamine D2 receptor have been characterized, D2L (long) and D2S (short), generated by alternative splicing from the same gene. They differ by an in-frame insert of 29 amino acids specific to D2L within the putative third intracytoplasmic loop of the receptor. We have previously demonstrated (Montmayeur, J.-P., Guiramand, J., and Borelli, E. (1993) Mol. Endocrinol. 7, 161-170) that D2S and D2L, although presenting very similar pharmacological profiles, couple differently to the alpha-subunit of guanine nucleotide-binding regulatory proteins (G-proteins). In particular, D2L, but not D2S, requires the presence of the alpha-subunit of the inhibitory G-protein (G alpha i2) to elicit greater inhibition of adenylyl cyclase activity. The insert present in D2L must therefore confer the specificity of interaction with G alpha i2. Thus, we introduced substitution mutations within the D2L insert. These mutant receptors were expressed in JEG3 cells, a G alpha i2-deficient cell line, scoring for those presenting an increased inhibition of adenylyl cyclase by dopamine. Our analysis identified two mutants, S259/262A and D249V, with these properties. These results clearly show that the insert present in D2L plays a critical role in the selectivity for the G-proteins interacting with the receptor.

Published
1995
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