Effect of Adrenomedullin Administration in Two Rat Models of Experimental Inflammatory Bowel Disease

Abstract

Adrenomedullin (AM) is a novel hypotensive peptide that also exerts powerful anti-inflammatory effects. We recently showed that AM significantly reduces the clinical severity of acetic acid-induced colitis, an experimental model of inflammatory bowel disease (IBD) in rats. In the present study, we examined the effect of AM in two alternative rat models of IBD. We found that 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced megacolon development in the saline-treated group, but AM treatment reduced the macroscopic damage caused by TNBS. In the dextran sulfate sodium (DSS) model, treatment with AM reduced diarrhea and bloody stool scores, but did not reduce body weight. Histological analysis revealed that in both the TNBS and DSS models, colon inflammation was much more severe in the saline-treated group than in the AM-treated group. These findings indicate that the anti-inflammatory properties of AM make it an effective therapeutic agent for the treatment of IBD in rats.

Anti‐Inflammatory Effects of PEGylated Human Adrenomedullin in a Mouse DSS‐Induced Colitis Model

“…In this report, we describe the effect of PEG‐hAM treatment on the DSS mouse model of colitis. In our previous studies, we found that hAM improves acetic acid‐induced colitis [Ashizuka et al, ], and TNBS‐ and DSS‐induced colitis in rats [Nagata et al, ]. Similarly, in the reserpine‐ and ethanol‐induced gastric lesion models, hAM exerts gastroprotective effects [Kaneko et al, ; Clementi et al, ; Salomone et al, ].…”

“…In our previous studies, hAM improved IBD in acetic acid, TNBS, and DSS models of colitis in rats [Ashizuka et al, ; Ashizuka et al, ; Nagata et al, ]. In addition, in patients with active refractory ulcerative colitis (UC) iv infusion of hAM for 8 h daily for 14 days, ameliorated the Disease Activity Index [Ashizuka et al, ].…”

Development of Long-Acting Human Adrenomedullin Fc-Fusion Proteins

“…As it is safe, inexpensive, and requires a small number of administrations, it might be available to many patients. AM was effective in a variety of disease model animals, including inflammatory bowel disease [ 2 ], ischemic heart disease [ 3 ], sepsis, and stroke [ 4 ]. Therefore, it might be applied to diseases for which treatment has been reported in AM.…”

“…Both of these structures are necessary for binding to receptors and to exert their biological functions. AM has pluripotent bioactivities, including vasodilatation, hormone secretion, wound healing, and anti-inflammation, which were associated with its beneficial pharmacological effects observed in various animal disease models, including inflammatory bowel disease [ 2 ], ischemic heart disease [ 3 ], sepsis [ 4 ], and stroke [ 5 ]. However, native AM has poor pharmacokinetic properties due to its rapid clearance and proteolytic degradation.…”