In a Methotrexate-Induced Model of Intestinal Mucositis, Olmesartan Reduced Inflammation and Induced Enteropathy Characterized by Severe Diarrhea, Weight Loss, and Reduced Sucrose Activity

Abstract

The aim of this study was to evaluate the effect of olmesartan (OLME), an angiotensin II receptor antagonist, on an intestinal mucositis model. Briefly, daily intraperitoneal (i.p.) injections of methotrexate (MTX) 7 mg/kg were administered to rats on 3 consecutive days. A subset of these rats was also pretreated with oral administration of OLME (0.5, 1.0, or 5.0 mg/kg) or vehicle as a control 30 min prior to MTX injection. Body weight, feces scoring, and death were recorded daily. On day 4, the rats were killed, and intestinal tissues were assayed for levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, myeloperoxidase and sucrose activity, and histopathological findings. A significant reduction in body weight was observed in the MTX 1.0 mg/kg OLME group (p<0.01). The feces scores for the MTX 0.5 mg/kg OLME and MTX 5.0 mg/ kg OLME groups were also significantly higher (p<0.001). Sucrose activity was reduced in all groups treated with OLME (p<0.05). Treatment with MTX OLM at all doses resulted in reduced inflammatory infiltration, ulcerations, vasodilation, and hemorrhagic areas ( p<0.05), as well as reduced concentrations of myeloperoxidase (p<0.001). The IL-1β and TNF-α levels were decreased in the MTX OLME 5.0 mg/kg (p<0.01 and p<0.05, respectively) compared with the MTX-alone group. Overall, antiinflammatory activity was observed in rats with MTX-induced intestinal mucositis that were administered OLME. However, further studies are needed to elucidate the adverse effects of OLME. Key words intestinal mucositis model; olmesartan; inflammationIt has been reported that 40% of cancer patients develop intestinal mucositis during a standard cancer chemotherapy regimen, while almost 100% of patients who receive high dose treatments are affected.1) Mucositis represents a dose-limiting toxicity of therapy and it currently affects approximately 500000 patients annually worldwide.2) The entire alimentary tract (mouth to anus) is affected, which leads to clinical symptoms that derive from ulcerations, and these include abdominal pain, nausea, vomiting, bloating, diarrhea, constipation, and subsequent weight loss.3) Furthermore, these complications can lead to longer hospitalisations and increasing health care costs. 4)Methotrexate (MTX) is a structural analogue of folic acid and is widely used in the treatment of leukaemia and other malignancies. Tissues with high rates of proliferation are affected by MTX, and these can include both tumor and normal tissues. When MTX affects gut tissues, gastrointestinal mucositis develops. Correspondingly, approximately 60% of cancer patients that receive a chemotherapy treatment that includes MTX experience diarrhoea. 5)The currently accepted hypothesis for the development of alimentary mucositis (AM) suggests there are five intertwined phases: (1) initiation, (2) up-regulation and generation of messenger signals, (3) signal amplification, (4) ulceration, and (5) healing.6) Data from both animal and human studies support this hypothesis.7-9) Furthermore, these same phases...

The effect of hippophae rhamnoides extract on oral mucositis induced in rats with methotrexate

“…Chang CT noted that the levels of proinflammatory cytokines, such as IL-1β and TNF-α, were elevated in the oral tissue with mucositis developed due to chemotherapy 8 . Another study shows that the levels of IL-1β and TNF-α were increased and inflammatory ulcers were developed in the intestinal tissue with MTX 3 . In this study, IL-1β and TNF-α gene expressions were significantly increased in the tissues in which MDA was significantly increased.…”

Effect of Hippophae rhamnoides Extract on Oxidative Oropharyngeal Mucosal Damage Induced in Rats Using Methotrexate

“…Logan and colleagues demonstrated that IL-1β and TNF-α are increased in mucositis related to MTX and other chemotherapy medications [27]. de Araujo et al [28] stated that inflammation was developed in an MTX mucositis model where proinflammatory cytokines, such as IL-1β and TNF-α, were implicated. This information suggests that inflammation and oxidative stress developed due to MTX in the oropharyngeal tissue in our study.…”

Effects of nimesulide on the small intestine mucositis induced by methotrexate in rats

“…MTX was reported to cause hyperemia, inflammatory cell infiltration and loss of villus epithelial cells in the small intestines of rats [6]. In another study, MTX has been reported to lead to the cellular loss, severe villus atrophy and PMNL leukocyte infiltration [7]. In addition to these histopathological findings, MTX is known to cause intestinal hemorrhage [18].…”