The present study examined the inhibitory effect of licorice compounds glycyrrhizin and a metabolite 18Ղ-glycyrrhetinic acid on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse and on the 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in differentiated PC12 cells. MPTP treatment increased the activities of total superoxide dismutase, catalase and glutathione peroxidase and the levels of malondialdehyde and carbonyls in the brain compared to control mouse brain. Co-administration of glycyrrhizin (16.8 mg/kg) attenuated the MPTP effect on the enzyme activities and formation of tissue peroxidation products. In vitro assay, licorice compounds attenuated the MPP+-induced cell death and caspase-3 activation in PC12 cells. Glycyrrhizin up to 100ՌM significantly attenuated the toxicity of MPP+. Meanwhile, 18Ղ-glycyrrhetinic acid showed a maximum inhibitory effect at 10ՌM; beyond this concentration the inhibitory effect declined. Glycyrrhizin and 18Ղ-glycyrrhetinic acid attenuated the hydrogen peroxide- or nitrogen species-induced cell death. Results from this study indicate that glycyrrhizin may attenuate brain tissue damage in mice treated with MPTP through inhibitory effect on oxidative tissue damage. Glycyrrhizin and 18Ղ-glycyrrhetinic acid may reduce the MPP+ toxicity in PC12 cells by suppressing caspase-3 activation. The effect seems to be ascribed to the antioxidant effect.