Olmesartan Decreased Levels of IL-1β and TNF-α, Down-Regulated MMP-2, MMP-9, COX-2, RANK/RANKL and Up-Regulated SOCs-1 in an Intestinal Mucositis Model

Abstract

Methotrexate (MTX) is a pro-oxidant compound that depletes dihydrofolate pools and is widely used in the treatment of leukaemia and other malignancies. The efficacy of methotrexate is often limited by mucositis and intestinal injury, which are major causes of morbidity in children and adults. The aim of this study was to evaluate the effect of olmesartan (OLM), an angiotensin II receptor antagonist, on an Intestinal Mucositis Model (IMM) induced by MTX in Wistar rats. IMM was induced via intraperitoneal (i.p.) administration of MTX (7 mg/kg) for three consecutive days. The animals were pre-treated with oral OLM at 0.5, 1 or 5 mg/kg or with vehicle 30 min prior to exposure to MTX. Small intestinal homogenates were assayed for levels of the IL-1β, IL-10 and TNF-α cytokines, malondialdehyde and myeloperoxidase activity. Additionally, immunohistochemical analyses of MMP-2, MMP-9, COX-2, RANK/RANKL and SOCS-1 and confocal microscopy analysis of SOCS-1 expression were performed. Treatment with MTX + OLM (5 mg/kg) resulted in a reduction of mucosal inflammatory infiltration, ulcerations, vasodilatation and haemorrhagic areas (p<0.05) as well as reduced concentrations of MPO (p<0.001) and the pro-inflammatory cytokines IL-1β (p<0.001) and TNF-a (p<0.01), and increase anti-inflammatory cytocine IL-10 (p<0.05). Additionally, the combined treatment reduced expression of MMP-2, MMP-9, COX-2, RANK and RANKL(p<0.05) and increased cytoplasmic expression of SOCS-1 (p<0.05). Our findings confirm the involvement of OLM in reducing the inflammatory response through increased immunosuppressive signalling in an IMM. We also suggest that the beneficial effect of olmesartan treatment is specifically exerted during the damage through blocking inflammatory cytocines.

Protective effect of angiotensin II receptor blocker against oxidative stress and inflammation in an oral mucositis experimental model

“…Our group have recently demonstrated the effect of azilsartan, an angiotensin II receptor antagonist, on the prevention of the mucosal damage and inflammation associated with 5‐FU‐induced oral mucositis model in hamsters . In addition, we also demonstrated the anti‐inflammatory effects of olmesartan on methotrexate‐induced intestinal mucositis in rats …”

“…The conventional RAS (Renin‐angiotensin system) has been viewed as a classical hormonal system comprising the enzymatic c leavage of the decapeptide angiotensin I (Ang I) by angiotensin‐converting enzyme (ACE) to the formation of Ang II, the principal effector peptide of RAS, which contributes to the regulation of blood pressure . Studies have, however, documented new roles for Ang II as a key regulator of inflammation and tissue injury …”

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