Effect of Oral Glutamine on Enterocyte Turnover during Methotrexate-Induced Mucositis in Rats

Sukhotnik, Igor; Karry, Rachel; Shamian, Benhoor; Lurie, M.; Kokhanovsky, Natalie; Ure, Benno M.; Coran, Arnold G.

doi:10.1159/000191209

Cited by 23 publications

(16 citation statements)

References 34 publications

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“…However, the clinical application of this agent is often limited by side effects such as nausea, vomiting, diarrhea, stomatitis, gastrointestinal ulceration and mucositis. These side effects are probably due to inhibition of the synthesis of dihydrofolate reductase which is essential to maintain the cellular tetrahydrofolate pool during purine and thymidine synthesis [1]. Being a high affinity inhibitor of dihydrofolate reductase, MTX is a pro-oxidant com- pound that causes depletion of the dihydrofolate pool and directly affects the synthesis of thymidilate, suppressing DNA synthesis.…”

Section: Introductionmentioning

confidence: 99%

Protective role of lipoic acid on methotrexate induced intestinal damage in rabbit model

Somi

Hajipour

Abad

et al. 2011

Indian J Gastroenterol

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Methotrexate (MTX), a folate antagonist agent, is mainly used in treatment of malignant tumors and auto immune diseases and affects not only tumor cells, but also gastrointestinal mucosa. The present study was undertaken to determine whether lipoic acid (LA) could ameliorate methotrexate-induced oxidative intestine injury in rabbits. Twenty-one rabbits were randomly assigned into three groups: Group 1 (control group), Group 2 (received 20 mg/kg MTX), Group 3 (received MTX plus LA 75 mg/kg orally). On the 6th day rabbits were anesthetized and intestinal tissue sampled for pathologic and biochemical assessment. The intestinal tissue injury index and malondialdehyde (MDA) levels were lower in MTX+LA group as compared to the MTX group, and tissue glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity were higher in MTX+LA group than in the MTX group (p < 0.05). These findings suggest that co-administration of LA with MTX is associated with reduction in oxidative injury and tissue damage in the intestine. We suggest that lipoic acid may have a protective role in the MTX-induced oxidative injury.

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Section: Introductionmentioning

confidence: 99%

Protective role of lipoic acid on methotrexate induced intestinal damage in rabbit model

Somi

Hajipour

Abad

et al. 2011

Indian J Gastroenterol

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“…In addition, glutamine exerts a positive effect on the gut-associated lymphoid tissue and enhances gut barrier function. We have demonstrated recently that administration of enteral glutamine prevents intestinal mucosal damage and accelerates intestinal recovery following methotrexate-induced mucositis in a rat [15]. In this study, we showed that treatment with glutamine attenuates alterations in TLR-4, MyD88 and TRAF6 intestinal expression during LPS endotoxemia in a rat [16].…”

Section: Introductionmentioning

confidence: 54%

“…We have shown that treatment with oral glutamine prevents mucosal injury and improves intestinal recovery following MTX- injury in the rat [14]. In this other experiment, we demonstrated a correlation between gut trophic effects of glutamine and its stimulating effect on TLR signaling during lipopolysaccharide endotoxemia in a rat [15]. …”

Section: Discussionmentioning

confidence: 97%

Glutamine attenuates the inhibitory effect of methotrexate on TLR signaling during intestinal chemotherapy-induced mucositis in a rat

et al. 2014

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Toll-like receptor 4 (TLR-4) is crucial in maintaining intestinal epithelial homeostasis, participates in a vigorous signaling process and heightens inflammatory cytokine output. The objective of this study was to determine the effects of glutamine (GLN) on TLR-4 signaling in intestinal mucosa during methotrexate (MTX)-induced mucositis in a rat. Male Sprague–Dawley rats were randomly assigned to one of four experimental groups of 8 rats each: 1) control rats; 2) CONTR-GLN animals were treated with oral glutamine given in drinking water (2%) 48 hours before and 72 hours following vehicle injection; 3) MTX-rats were treated with a single IP injection of MTX (20 mg/kg); and 4) MTX-GLN rats were pre-treated with oral glutamine similar to group B, 48 hours before and 72 hours after MTX injection. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 hours following MTX injection. The expression of TLR-4, MyD88 and TRAF6 in the intestinal mucosa was determined using real time PCR, Western blot and immunohistochemistry. MTX-GLN rats demonstrated a greater jejunal and ileal mucosal weight and mucosal DNA, greater villus height in ileum and crypt depth and index of proliferation in jejunum and ileum, compared to MTX animals. The expression of TLR-4 and MyD88 mRNA and protein in the mucosa was significantly lower in MTX rats versus controls animals. The administration of GLN increased significantly the expression of TLR-4 and MyD88 (vs the MTX group). In conclusion, treatment with glutamine was associated with up-regulation of TLR-4 and MyD88 expression and a concomitant decrease in intestinal mucosal injury caused by MTX-induced mucositis in a rat.

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“…l -Glutamine encourages protein synthesis, enterocyte proliferation and anti-inflammatory effects, all of which play a role in prevention of mucositis [15,16,17]. It has also been shown that supplemental glutamine (as an oral gavage) assists uptake of methotrexate into tumor tissue (in studies in rats), increasing tumoricidal effects, while decreasing MTX-associated side effects, such as gut toxicity [11].…”

Section: Introductionmentioning

confidence: 99%

“…Studies investigating Clinutren Protect ® [4,5], Modulen ® [6], TGF-β [3,7], and l -glutamine [11,17,18] for prevention of methotrexate-induced gut damage have been previously undertaken with success. However, it is known that tumor burden is associated with significantly increased chemotherapy-induced gut toxicity [19].…”

Section: Introductionmentioning

confidence: 99%

Investigation of Effect of Nutritional Drink on Chemotherapy-Induced Mucosal Injury and Tumor Growth in an Established Animal Model

et al. 2013

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Chemotherapy-induced mucositis represents a significant burden to quality of life and healthcare costs, and may be improved through enhanced nutritional status. We first determined the safety of two nutritional drinks (plus placebo), and then potential gut protection in tumor-bearing rats in a model of methotrexate-induced mucositis. In study 1, animals were fed one of two test diets (or placebo or control chow pellets) for a total of 60 days and were monitored daily. All diets were found to be safe to administer. In study 2, after seven days of receiving diets, a Dark Agouti Mammary Adenocarcinoma (DAMA) was transplanted subcutaneously. Ten days after starting diets, animals had 2 mg/kg intramuscular methotrexate administered on two consecutive days; after this time, all animals were given soaked chow. Animals were monitored daily for changes in bodyweight, tumor burden and general health. Animals were killed 10, 12 and 16 days after initially starting diets, and tissues were collected at necropsy. In study 1, animals receiving diets had gained 0.8% and 10.8% of their starting bodyweight after 60 days, placebo animals 4.4%, and animals fed on standard chow had gained 15.1%. In study 2, there was no significant influence of test diet on bodyweight, organ weight, tumor burden or biochemical parameters. Only animals treated with MTX exhibited diarrhea, although animals receiving Diet A and Diet C showed a non-significant increase in incidence of diarrhea. Administration of these nutritional drinks did not improve symptoms of mucositis.

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Effect of Oral Glutamine on Enterocyte Turnover during Methotrexate-Induced Mucositis in Rats

Cited by 23 publications

References 34 publications

Protective role of lipoic acid on methotrexate induced intestinal damage in rabbit model

Protective role of lipoic acid on methotrexate induced intestinal damage in rabbit model

Glutamine attenuates the inhibitory effect of methotrexate on TLR signaling during intestinal chemotherapy-induced mucositis in a rat

Investigation of Effect of Nutritional Drink on Chemotherapy-Induced Mucosal Injury and Tumor Growth in an Established Animal Model

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