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NEUROPHARMACOLOGY

The Bile Acid Tauroursodeoxycholic Acid Modulates Phosphorylation and Translocation of Bad via Phosphatidylinositol 3-Kinase in Glutamate-Induced Apoptosis of Rat Cortical Neurons

Centro de Patogénese Molecular, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal (R.E.C., S.S., R.M.R., C.M.P.R.); and Departments of Medicine (C.J.S.) and Genetics, Cell Biology, and Development (C.J.S.), University of Minnesota Medical School, Minneapolis, Minnesota

Neurotoxicity associated with increased glutamate release results in cell death through both necrotic and apoptotic processes. In addition, tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, is a strong modulator of apoptosis in several cell types. The aims of this study were to test the hypothesis that TUDCA reduces the apoptotic threshold induced by glutamate in rat cortical neurons and examine potential transduction pathways involved in both apoptotic signaling and neuroprotection by TUDCA. The results demonstrated that exposure of cortical neurons to glutamate induced cytochrome c release and caspase activation, as well as morphologic changes of apoptosis. These events were associated with down-regulation of antiapoptotic members of the Bcl-2 family, Bcl-2 and Bcl-x_L, and dephosphorylation of the serine/threonine protein kinase Akt. Pretreatment with TUDCA significantly reduced glutamate-induced apoptosis of rat cortical neurons. In addition, TUDCA induced marked phosphorylation and translocation of Bad from mitochondria to the cytosol. Moreover, inhibition of the phosphatidylinositol 3-kinase (PI3K) survival pathway abrogated the protective effects of TUDCA, including phosphorylation and translocation of Bad. In conclusion, TUDCA appears to modulate glutamate-induced neuronal apoptosis, in part, by activating a PI3K-dependent Bad signaling pathway. These data suggest that TUDCA may be beneficial in treating neurodegenerative disorders in which increased glutamate levels contribute to the pathogenesis of the disease.

Address correspondence to: Cecília M. P. Rodrigues, Av. das Forças Armadas, 1600-083 Lisbon, Portugal. E-mail: cmprodrigues{at}ff.ul.pt

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