title: Inhibition of α2A-Adrenoceptors Ameliorates Dextran Sulfate Sodium-Induced Acute Intestinal Inflammation in Mice.
abstract: It has been hypothesized that α2-adrenoceptors (α2-ARs) may be involved in the pathomechanism of colitis; however, the results are conflicting because both aggravation and amelioration of colonic inflammation have been described in response to α2-AR agonists. Therefore, we aimed to analyze the role of α2-ARs in acute murine colitis. The experiments were carried out in wild-type, α2A-, α2B-, and α2C-AR knockout (KO) C57BL/6 mice. Colitis was induced by dextran sulfate sodium (DSS, 2%); alpha2-AR ligands were injected i.p. The severity of colitis was determined both macroscopically and histologically. Colonic myeloperoxidase (MPO) and cytokine levels were measured by enzyme-linked immunosorbent assay and proteome profiler array, respectively. The nonselective α2-AR agonist clonidine induced a modest aggravation of DSS-induced colitis. It accelerated the disease development and markedly enhanced the weight loss of animals, but did not influence the colon shortening, tissue MPO levels, or histologic score. Clonidine induced similar changes in α2B- and α2C-AR KO mice, whereas it failed to affect the disease activity index scores and caused only minor weight loss in α2A-AR KO animals. In contrast, selective inhibition of α2A-ARs by BRL 44408 significantly delayed the development of colitis; reduced the colonic levels of MPO and chemokine (C-C motif) ligand 3, chemokine (C-X-C motif) ligand 2 (CXCL2), CXCL13, and granulocyte-colony stimulating factor; and elevated that of tissue inhibitor of metalloproteinases-1. In this work, we report that activation of α2-ARs aggravates murine colitis, an effect mediated by the α2A-AR subtype, and selective inhibition of these receptors reduces the severity of gut inflammation.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.) zadori.zoltan@med.semmelweis-univ.hu.
authors.forename: Zoltán S
authors.identifier: 0000-0001-7312-618X
authors.initials: ZS
authors.lastname: Zádori
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Viktória E
authors.initials: VE
authors.lastname: Tóth
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Fehér
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Khrasani
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Zita
authors.initials: Z
authors.lastname: Puskár
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Márk
authors.initials: M
authors.lastname: Kozsurek
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Júlia
authors.initials: J
authors.lastname: Timár
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Tamás
authors.initials: T
authors.lastname: Tábi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Peter
authors.initials: P
authors.lastname: Holzer
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.).
authors.forename: Klára
authors.initials: K
authors.lastname: Gyires
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D003000:Clonidine / Q000494:pharmacology / Q000627:therapeutic use; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016264:Dextran Sulfate / Q000494:pharmacology*; D004326:Drinking / Q000187:drug effects; D005260:Female; D055786:Gene Knockout Techniques; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D054833:Isoindoles / Q000494:pharmacology / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D007093:Imidazoles; D054833:Isoindoles; D018341:Receptors, Adrenergic, alpha-2; D016264:Dextran Sulfate; D003000:Clonidine; C072125:BRL 44408