PT  - JOURNAL ARTICLE
AU  - Zoltán S. Zádori
AU  - Viktória E. Tóth
AU  - Ágnes Fehér
AU  - Mahmoud Al-Khrasani
AU  - Zita Puskár
AU  - Márk Kozsurek
AU  - Júlia Timár
AU  - Tamás Tábi
AU  - Zsuzsanna Helyes
AU  - Lutz Hein
AU  - Peter Holzer
AU  - Klára Gyires
TI  - Inhibition of α<sub>2A</sub>-Adrenoceptors Ameliorates Dextran Sulfate Sodium–Induced Acute Intestinal Inflammation in Mice
AID  - 10.1124/jpet.116.235101
DP  - 2016 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 483--491
VI  - 358
IP  - 3
4099  - http://jpet.aspetjournals.org/content/358/3/483.short
4100  - http://jpet.aspetjournals.org/content/358/3/483.full
SO  - J Pharmacol Exp Ther2016 Sep 01; 358
AB  - 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.