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Tauroursodeoxycholic Acid Partially Prevents Apoptosis Induced by 3‐Nitropropionic Acid
Author(s) -
Rodrigues Cecilia M. P.,
Stieers Cheryle Linehan,
Keene C. Dirk,
Ma Xiaoming,
Kren Betsy T.,
Low Walter C.,
Steer Clifford J.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0752368.x
Subject(s) - tauroursodeoxycholic acid , apoptosis , programmed cell death , cytochrome c , biology , mitochondrial permeability transition pore , taurine , mitochondrion , biochemistry , endocrinology , amino acid , unfolded protein response
Ursodeoxycholic acid (UDCA) has been shown to be a strongmodulator of the apoptotic threshold in both hepatic and nonhepatic cells.3‐Nitropropionic acid (3‐NP), an irreversible inhibitor of succinatedehydrogenase, appears to cause apoptotic neuronal cell death in the striatum,reminiscent of the neurochemical and anatomical changes associated withHuntington's disease (HD). This study was undertaken (a) to characterizefurther the mechanism by which 3‐NP induces apoptosis in rat neuronal RN33Bcells and (b) to determine if and how the taurine‐conjugated UDCA,tauroursodeoxycholic acid (TUDCA), inhibits apoptosis induced by 3‐NP. Ourresults indicate that coincubation of cells with TUDCA and 3‐NP was associatedwith an ∼80% reduction in apoptosis ( p < 0.001), whereasneither taurine nor cyclosporin A, a potent inhibitor of the mitochondrialpermeability transition (MPT), inhibited cell death. Moreover, TUDCA, as wellas UDCA and its glycine‐conjugated form, glycoursodeoxycholic acid, preventedmitochondrial release of cytochrome c ( p < 0.001), whichprobably accounts for the observed inhibition of DEVD‐specific caspaseactivity and poly(ADP‐ribose) polymerase cleavage. 3‐NP decreasedmitochondrial transmembrane potential ( p < 0.001) and increasedmitochondrial‐associated Bax protein levels ( p < 0.001).Coincubation with TUDCA was associated with significant inhibition of thesemitochondrial membrane alterations ( p < 0.01). The results suggestthat TUDCA inhibits 3‐NP‐induced apoptosis via direct inhibition ofmitochondrial depolarization and outer membrane disruption, together withmodulation of Bax translocation from cytosol to mitochondria. In addition,cell death by 3‐NP apparently occurs through pathways that are independent ofthe MPT.