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NEUROPHARMACOLOGY

Protective Effect of Glycyrrhizin on 1-Methyl-4-phenylpyridinium-Induced Mitochondrial Damage and Cell Death in Differentiated PC12 Cells

Department of Neurology, Gangneung Asan Hospital, College of Medicine, University of Ulsan, Gangwon-do, South Korea (S.B.Y.); and Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, South Korea (S.B.Y., S.E.P., C.S.L.)

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⁺) in relation to the mitochondria-mediated cell death process and role of oxidative stress. MPP⁺ 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 µM significantly attenuated cell death and depletion of GSH due to MPP⁺ concentration-dependently. Meanwhile, 18-glycyrrhetinic acid showed a maximal inhibitory effect at 10 µM; 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⁺-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⁺ toxicity. Glycyrrhizin and 18-glycyrrhetinic acid may prevent the cytotoxicity of MPP⁺ 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.

Address correspondence to: Dr. Chung Soo Lee, Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea. E-mail: leecs{at}cau.ac.kr