Analysing the effect of I1 imidazoline receptor ligands on DSS-induced acute colitis in mice

Abstract

Imidazoline receptors (IRs) have been recognized as promising targets in the treatment of numerous diseases, and moxonidine and rilmenidine, agonists of I1-IRs are widely used as antihypertensive agents. Some evidence suggests that IR ligands may induce anti-inflammatory effects acting on I1-IRs or other molecular targets, which could be beneficial in patients with inflammatory bowel disease (IBD). On the other hand, several IR ligands may stimulate also alpha2-adrenoceptors, which was earlier shown to inhibit, but in more recent studies to rather aggravate colitis. Hence, this study aimed to analyse for the first time the effect of various I1-IR ligands on intestinal inflammation. Colitis was induced in C57BL/6 mice by adding dextran sulfate sodium (DSS) to the drinking water for 7 days. Mice were treated daily with different IR ligands; moxonidine and rilmenidine (I1-IR agonists), AGN 192403 (highly selective I1-IR ligand, putative antagonist), efaroxan (I1-IR antagonist), as well as with the endogenous IR agonists agmatine and harmane. It was found that moxonidine and rilmenidine at clinically relevant doses, similarly to the other IR ligands, do not have a significant impact on the macroscopic and histological signs of DSS-evoked inflammation. Likewise, colonic myeloperoxidase and serum interleukin-6 levels remained unchanged in response to these agents. Thus, our study demonstrates that imidazoline ligands do not influence significantly the severity of DSS-colitis in mice and suggest that they probably neither affect the course of IBD in humans. However, the translational value of these findings needs to be verified with other experimental colitis models and human studies.

Activation of imidazoline I1 receptor by moxonidine regulates the progression of liver fibrosis in the Nrf2-dependent pathway

“…I 1 R is involved in the regulation of behavioral disorders and the pathogenesis of many diseases, such as hypertension, obesity, and Huntington's disease [18][19][20]. Modulators of I 1 R have been reported to exhibit multiple pharmaceutical potentials including suppressing inflammation, anti-diabetes and cytoprotection [21,22]. However, to date, the potential role of I 1 R in treatment of liver fibrosis has not been reported.…”