Reactive oxygen species (ROS) are increased in inflammatory bowel disease (IBD) and have been implicated as mediators of intestinal inflammation. We investigated the hypothesis that antioxidants with diverse properties attenuate disease progression in a murine dextran sodium sulfate (DSS)-induced colitis model. These antioxidants were (A) S-adenosylmethionine, a glutathione (GSH) precursor; (B) green tea polyphenols, a well-known antioxidant; and (C) 2(R,S)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA), a cysteine prodrug, involved in GSH biosynthesis. BALB/c mice were divided into four groups and provided with the above mentioned antioxidants or the vehicle incorporated into chow. The animals were further divided into two subgroups and given normal drinking water (control) or water supplemented with DSS (to induce colitis), and the progression of the disease was studied. DSS-treated mice developed severe colitis as shown by bloody diarrhea, weight loss and pathological involvement (P<.001). However, all the antioxidants significantly improved diarrhea and colon lesions (P<.01), and increased body weights (P<.05). Hematocrits were significantly less affected in DSS-treated animals receiving antioxidants (P<.01). Colon lengths were significantly decreased due to mucosal inflammation in DSS-treated animals, but antioxidant therapy normalized this pathological finding (P<.001). The blood level of reduced GSH was decreased in DSS-treated mice (P<.05) and returned to normal when treated with antioxidants. Serum amyloid A (acute phase protein; P=.0015) and tumor necrosis factor-alpha (TNF-alpha; pro-inflammatory cytokine; P<.01) were significantly increased in DSS-treated animals (161+/-40 pg/ml) and improved with antioxidant treatment (P<.01). Finally, actin cytoskeleton was distorted and fragmented in the mucosa of DSS-treated mice and improved with antioxidant therapy. In conclusion, three structurally dissimilar antioxidants provided protection against DSS-induced colitis in this murine model, supporting a possible role for antioxidant therapy in IBD patients.