Inhibition of α2A-Adrenoceptors Ameliorates Dextran Sulfate Sodium-Induced Acute Intestinal Inflammation in Mice

Z. Zádori, Viktória E. Tóth, Ágnes Fehér, M. Al-Khrasani, Z. Puskár, Márk Kozsurek, Júlia Timár, T. Tábi, Z. Helyes, Lutz Hein, Peter Holzer, K. Gyires

Research output: Contribution to journalArticle

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Abstract

It has been hypothesized that α2- Adrenoceptors (a2-ARs) may be involved in the pathomechanismof colitis; however, the results are conflicting because both aggravation and amelioration of colonic inflammation have been described in response to a2-AR agonists. Therefore, we aimed to analyze the role of α2A-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%); α2-AR ligands were injected i.p. The severity of colitis was determined both macroscopically and histologically. Colonicmyeloperoxidase (MPO) and cytokine levels weremeasured by enzyme-linked immunosorbent assay and proteome profiler array, respectively. The nonselective α2-AR agonist clonidine induced a modest aggravation of DSSinduced 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 granulocytecolony 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.

Original languageEnglish
Pages (from-to)483-491
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume358
Issue number3
DOIs
Publication statusPublished - Sep 1 2016

Fingerprint

Dextran Sulfate
Colitis
Adrenergic Receptors
Inflammation
Clonidine
Knockout Mice
Weight Loss
Chemokine CXCL2
Chemokine CCL3
Tissue Inhibitor of Metalloproteinase-1
Proteome
Inbred C57BL Mouse
Colon
Enzyme-Linked Immunosorbent Assay
Cytokines
Ligands

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Pharmacology

Cite this

Inhibition of α2A-Adrenoceptors Ameliorates Dextran Sulfate Sodium-Induced Acute Intestinal Inflammation in Mice. / Zádori, Z.; Tóth, Viktória E.; Fehér, Ágnes; Al-Khrasani, M.; Puskár, Z.; Kozsurek, Márk; Timár, Júlia; Tábi, T.; Helyes, Z.; Hein, Lutz; Holzer, Peter; Gyires, K.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 358, No. 3, 01.09.2016, p. 483-491.

Research output: Contribution to journalArticle

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abstract = "It has been hypothesized that α2- Adrenoceptors (a2-ARs) may be involved in the pathomechanismof colitis; however, the results are conflicting because both aggravation and amelioration of colonic inflammation have been described in response to a2-AR agonists. Therefore, we aimed to analyze the role of α2A-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{\%}); α2-AR ligands were injected i.p. The severity of colitis was determined both macroscopically and histologically. Colonicmyeloperoxidase (MPO) and cytokine levels weremeasured by enzyme-linked immunosorbent assay and proteome profiler array, respectively. The nonselective α2-AR agonist clonidine induced a modest aggravation of DSSinduced 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 granulocytecolony 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.",
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AU - Fehér, Ágnes

AU - Al-Khrasani, M.

AU - Puskár, Z.

AU - Kozsurek, Márk

AU - Timár, Júlia

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