Ursodeoxycholic acid suppresses mitochondria-dependent programmed cell death induced by sodium nitroprusside in SH-SY5Y cells

• Published in: Toxicology (Amsterdam) 2012-02, Vol.292 (2-3), p.105-112
• Main Authors: Chun, Hong Sung, Low, Walter C
• Format: Article
• Language: English
• Subjects: Apoptosis; Cell Death - drug effects; Cell Line; Chromones - pharmacology; cytochrome c; cytotoxicity; Dopaminergic cell; Dopaminergic Neurons - metabolism; Emergency; glutathione; Glutathione - analysis; Glutathione - metabolism; Humans; Immunoblotting; membrane potential; Membrane Potential, Mitochondrial - drug effects; mitochondrial membrane; Morpholines - pharmacology; nitric oxide; Nitric Oxide - analysis; Nitric Oxide - metabolism; nitroprusside; Nitroprusside - metabolism; Nitroprusside - toxicity; Parkinson disease; Peroxynitrous Acid - analysis; Peroxynitrous Acid - metabolism; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; protective effect; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; reactive oxygen species; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; SNP; toxicology; Ursodeoxycholic acid; Ursodeoxycholic Acid - pharmacology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2011.11.020

Abstract Although ursodeoxycholic acid (UDCA) and its highly water-soluble formula (Yoo's solution; YS) have been shown to prevent neuronal damage, the effects of UDCA or YS against Parkinson's disease (PD)-related dopaminergic cell death has not been studied. This study investigated the protective effects of UDCA and YS on sodium nitroprusside (SNP)-induced cytotoxicity in human dopaminergic SH-SY5Y cells. Both UDCA (50–200 μM) and YS (100–200 μM) dose-dependently prevented SNP (1 mM)-induced cell death. Results showed that both UDCA and YS effectively attenuated the production of total reactive oxygen species (ROS), peroxynitrite (ONOO− ) and nitric oxide (NO), and markedly inhibited the mitochondrial membrane potential (MMP) loss and intracellular reduced glutathione (GSH) depletion. SNP-induced programmed cell death events, such as nuclear fragmentation, caspase-3/7 and -9 activation, Bcl-2/Bax ratio decrease, and cytochrome c release, were significantly attenuated by both UDCA and YS. Furthermore, selective inhibitor of phosphatidylinositiol-3-kinase (PI3K), LY294002, and Akt/PKB inhibitor, triciribine, reversed the preventive effects of UDCA on the SNP-induced cytotoxicity and Bax translocation. These results suggest that UDCA can protect SH-SY5Y cells under programmed cell death process by regulating PI3K-Akt/PKB pathways.