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, α_2A-, α_2B-, and α_2C-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 α_2B- and α_2C-AR KO mice, whereas it failed to affect the disease activity index scores and caused only minor weight loss in α_2A-AR KO animals. In contrast, selective inhibition of α_2A-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 α_2A-AR subtype, and selective inhibition of these receptors reduces the severity of gut inflammation.