Inhibition of alpha2A-adrenoceptors ameliorates DSS-induced acute intestinal inflammation in mice

Abstract

It has been hypothesized that alpha2-adrenoceptors (alpha2-ARs) may be involved in the pathomechanism of colitis, however, the results are conflicting since both aggravation and amelioration of colonic inflammation have been described in response to alpha2-AR agonists. Therefore, we aimed to analyse the role of alpha2-ARs in acute murine colitis. The experiments were carried out in wild-type (WT), alpha2A-, alpha2B- and alpha2C-AR knockout (KO) C57BL/6 mice. Colitis was induced by dextran sulfate sodium (DSS, 2 %), alpha2-AR ligands were injected intraperitoneally (i.p.). The severity of colitis was determined both macroscopically and histologically. Colonic myeloperoxidase (MPO) and cytokine levels were measured by ELISA and proteome profiler array, respectively. The non-selective alpha2-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 histological score. Clonidine induced similar changes in alpha2B- and alpha2C-AR KO mice, whereas it failed to affect the disease activity index (DAI) scores and caused only minor weight loss in alpha2A-AR KO animals. On the other hand, selective inhibition of alpha2A-ARs by BRL 44408 significantly delayed the development of colitis, reduced the colonic levels of MPO and the cytokines/chemokines CCL3, CXCL2, CXCL13 and G-CSF, and elevated that of TIMP-1. Here we report that activation of alpha2-ARs aggravates murine colitis, an effect mediated by the alpha2A-AR subtype, and selective inhibition of these receptors reduces the severity of gut inflammation.