S-adenosyl-L-methionine (SAM), used to treat liver diseases and as a coadjuvant in antidepressive medication, has neuroprotective effects in animal models. The aim of this study was to discover whether SAM has antioxidant effects in rat brain tissue. Ten male Wistar rats were killed by decapitation and the forebrains incubated with SAM for in vitro experiments. To study the effects of long-term administration, animals in four groups of ten rats each were given 10 mg SAM/kg per day s.c., and 40 other rats were given an equivalent volume of L-lysine (the commercial solvent for SAM). Treatment was started at the end of lactation, and animals were killed by decapitation after 15 days or 1, 6 or 22 months of treatment. The forebrain of each animal was used to test membrane lipid peroxidation by determining thiobarbituric acid-reactive substances (TBARS), glutathione level and enzyme activities related to glutathione (reduced form GSH, oxidized form GSSG) metabolism: GSH-peroxidase (GSHpx), GSSD-reductase (GSSGrd) and GSH-transferase (GSHtf). Chronic treatment with SAM decreased maximum forebrain production of TBARS by 46% compared with animals given L-lysine and increased glutathione levels by 50%, GSHpx activity by 115% and GSHtf activity by 81.4%. The results of in vitro experiments were qualitatively similar: lipid peroxidation was inhibited (13.1+/-1.3 nmol/mg protein in controls vs. 5.9+/-0.8 nmol/mg protein in samples incubated with 1000 micromol/l SAM) and glutathione levels were stimulated (0.97+/-0.06 micromol/g tissue in control samples vs. 1.55+/-0.08 micromol/g tissue in samples incubated with 1000 micromol/l SAM), as were GSHpx and GSHtf. No significant effect was seen in any of the experiments with L-lysine. We conclude that SAM has antioxidant effects in rat brain tissue both in vitro and ex vivo. The effect is seen both as inhibition of lipid peroxide production and as an enhancement of the endogenous glutathione antioxidant system.