Defects in mitochondrial function have been shown to participate in the induction of neuronal cell injury. The aim of the present study was to assess the preventive effect of licorice compounds glycyrrhizin and 18␤-glycyrrhetinic acid against the toxicity of parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP ϩ ) in relation to the mitochondria-mediated cell death process and role of oxidative stress. MPP ϩ induced the nuclear damage, the changes in the mitochondrial membrane permeability, leading to the cytochrome c release and caspase-3 activation, the formation of reactive oxygen species, and the depletion of glutathione (GSH) in differentiated PC12 cells. Glycyrrhizin up to 100 M significantly attenuated cell death and depletion of GSH due to MPP ϩ concentration-dependently. Meanwhile, 18␤-glycyrrhetinic acid showed a maximal inhibitory effect at 10 M; beyond this concentration, the inhibitory effect declined. The protective effect of licorice compounds was also detected in the rotenone-treated PC12 cells. Glycyrrhizin and 18␤-glycyrrhetinic acid prevented the MPP ϩ -induced formation of the mitochondrial permeability transition. The results show that both glycyrrhizin and a metabolite, 18␤-glycyrrhetinic acid, exhibit a depressant effect against the MPP ϩ toxicity. Glycyrrhizin and 18␤-glycyrrhetinic acid may prevent the cytotoxicity of MPP ϩ by suppressing the mitochondrial permeability transition formation. The preventive effect seems to be ascribed to the inhibitory effect on the formation of reactive oxygen species and depletion of GSH.Mitochondrial dysfunction and increased oxidative stress have been shown to be implicated in dopaminergic cell degeneration in Parkinson's disease (Jenner, 2003). In this disease, the major mitochondrial defect seems to be associated with complex I at the electron transport chain. Impairment of complex I activity leads to excess ROS formation, which causes mitochondrial dysfunction and cell death (Fleury et al., 2002;Jenner, 2003). Implication of oxidative stress in the pathogenesis and progression of Parkinson's disease is supported by the decrease in GSH content, increase in levels of lipid peroxidation products, increased production of ROS, and increase in iron content in substantia nigra (Olanow and Tatton, 1999).MPTP produces an irreversible and severe parkinsonianlike syndrome in human and nonhuman primates (Przedborski and Jackson- Lewis, 1998;Przedborski et al., 2000). The inhibition of complex I in the mitochondrial electron transport chain induced by MPP ϩ , the active metabolite of MPTP, results in impaired ATP production, loss of mitochondrial membrane potential, and formation of ROS (Cassarino et al., 1997;Schulz et al., 1997). The membrane permeability transition of mitochondria is known as a central event in the course of toxic and oxidative forms of cell injury, as well as apoptosis (Mignotte and Vayssière, 1998). Along with respiratory chain inhibition, MPP ϩ -induced neuronal cell death is suggested to be mediated by formation of the mitocho...

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