Leptin accelerates enterocyte turnover during methotrexate-induced intestinal mucositis in a rat model

Abstract

Gastrointestinal mucositis occurs as a consequence of cytotoxic treatment. In the present study, we tested whether leptin can protect gut epithelial cells from methotrexate (MTX)-induced intestinal damage. Non-pretreated and pretreated with MTX Caco-2 cells were incubated with increasing concentrations of leptin for 24 h. Cell proliferation and apoptosis were assessed using FACS analysis. Adult rats were divided into three experimental groups: Control rats; MTX-rats were treated with a single dose of MTX, and MTX-LEP rats were also treated with leptin for 3 d. Intestinal mucosal damage (Park score), mucosal structural changes (bowel and mucosal weight, mucosal DNA and protein content, villus height and crypt depth), enterocyte proliferation, and enterocyte apoptosis were measured at sacrifice. RT-PCR was used to determine the level of bax and bcl-2 mRNA expression. In the vitro experiment, treatment with leptin of Caco-2 cells pre-treated with MTX resulted in a significant stimulation of cell proliferation and inhibition of cell apoptosis in a dose-dependent manner. In the vivo experiment, MTX-LEP rats demonstrated a greater jejunal and ileal bowel and mucosal weight, mucosal DNA and protein, villus height and crypt depth, as well as a greater enterocyte proliferation index compared to MTX-animals. MTX-LEP rats also showed a trend toward an increase in enterocyte apoptosis that was accompanied by an increase in bax mRNA and decrease in bcl-2 mRNA expression. In conclusion, leptin enhances proliferation and decreases apoptosis in Caco-2 cells pretreated with MTX. In a rat model of MTX-induced mucositis, treatment with leptin improves intestinal recovery and enhances enterocyte turnover.

Oral Complications and Management Strategies for Patients Undergoing Cancer Therapy

“…Various studies have demonstrated the potential benefits of LLLT in its ability to reduce the rates of WHO severe grade mucositis [121, 122]. Other novel methods and experimental approaches include a formulation containing the amino acid L-glutamine and the hormone, leptin; both have been shown to have a positive impact on the development of mucositis [123–126]. …”

Oral complications in the treatment of cancer patients

“…Use of LLLT, utilizing an InGaAlP diode laser at a wavelength of 660‐nm, on chemotherapy patients with various cancers, including non‐Hodgkin’s Lymphoma, showed lower rates of severe grade WHO mucositis (Silva et al , 2010). Other experimental approaches include the hormone, leptin, which may accelerate enterocyte turnover and has been shown to beneficially impact the development of mucositis in rats treated with methotrexate (Sukhotnik et al , 2009b).…”

Effects of resveratrol on methotrexate-induced intestinal injury

“…Dihydrofolate reductase is an enzyme essential for DNA synthesis. In this way, DNA synthesis is impaired (3) and apoptosis takes place in the cells (3,36). While elevated Bax protein has been determined in MTX administrations, the level of Bcl 2 protein decreases (26).…”