title: Reversal of severe methotrexate-induced intestinal damage using enteral n-3 fatty acids.
abstract: Growing evidence suggests that n-3 PUFA and their specific lipid mediators can reduce the activity of inflammatory processes. In the present study, we evaluated the effects of oral n-3 PUFA supplementation on intestinal structural changes, enterocyte proliferation and apoptosis during methotrexate (MTX)-induced intestinal damage in the rat. A total of thirty-two male rats were divided into four experimental groups: control (CONTR) rats; CONTR-n-3 PUFA rats treated with oral administration of n-3 PUFA at a dose of 300 μg/kg once per d 72 h before and 72 h following vehicle injection; MTX rats treated with a single dose of MTX; MTX-n-3 PUFA rats treated with oral n-3 PUFA following the injection of MTX. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis determined 72 h following MTX injection. Real-time PCR was used to determine B-cell lymphoma 2 (Bcl2)-associated X protein (Bax) and Bcl2 mRNA expression. Western blotting was used to determine phosphorylated extracellular signal-related kinase, β-catenin, Bax and Bcl2 protein levels. MTX-n-3 PUFA rats demonstrated a greater jejunal and ileal bowel weight, greater ileal mucosal weight, greater ileal mucosal DNA and protein levels, greater villus height in the jejunum and ileum and crypt depth in the ileum, compared with MTX animals. A significant decrease in enterocyte apoptosis in the ileum of MTX-n-3 PUFA rats (v. MTX) was accompanied by decreased Bax mRNA and protein expression and increased Bcl2 mRNA levels. Thus, the treatment with oral n-3 PUFA prevented mucosal injury and improved intestinal recovery following MTX-injury in rats.
authors.affiliation: Laboratory of Intestinal Adaptation and Recovery, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Bnai Zion Medical Center, Haifa, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Koppelmann
authors.forename: Yulia
authors.initials: Y
authors.lastname: Pollak
authors.forename: Jorge
authors.initials: J
authors.lastname: Mogilner
authors.forename: Jacob
authors.initials: J
authors.lastname: Bejar
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Coran
authors.forename: Igor
authors.initials: I
authors.lastname: Sukhotnik
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019587:Dietary Supplements; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015525:Fatty Acids, Omega-3 / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D052016:Mucositis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009929:Organ Size / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C494828:Bax protein, rat; D015525:Fatty Acids, Omega-3; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D008727:Methotrexate