title: Beneficial effect of (-)schisandrin B against 3-nitropropionic acid-induced cell death in PC12 cells.
abstract: Huntington's disease (HD) is characterized by the dysfunction of mitochondrial energy metabolism, which is associated with the functional impairment of succinate dehydrogenase (mitochondrial complex II), and pyruvate dehydrogenase (PDH). Treatment with 3-nitropropionic acid (3-NP), a potent irreversible inhibitor of succinate dehydrogenase, replicates most of the pathophysiological features of HD. In the present study, we investigated the effect of (-)schisandrin B [(-)Sch B, a potent enantiomer of schisandrin B] on 3-NP-induced cell injury in rat differentiated neuronal PC12 cells. The 3-NP caused cell necrosis, as assessed by lactate dehydrogenase (LDH) leakage, and mitochondrion-dependent cell apoptosis, as assessed by caspase-3 and caspase-9 activation, in differentiated PC12 cells. The cytotoxicity induced by 3-NP was associated with a depletion of cellular reduced glutathione (GSH) as well as the activation of redox-sensitive c-Jun N-terminal kinase (JNK) pathway and the inhibition of PDH. (-)Sch B pretreatment (5 and 15 μM) significantly reduced the extent of necrotic and apoptotic cell death in 3-NP-challenged cells. The cytoprotection afforded by (-)Sch B pretreatment was associated with the attenuation of 3-NP-induced GSH depletion as well as JNK activation and PDH inhibition. (-)Sch B pretreatment enhanced cellular glutathione redox status and ameliorated the 3-NP-induced cellular energy crisis, presumably by suppressing the activated JNK-mediated PDH inhibition, thereby protecting against necrotic and apoptotic cell death in differentiated PC12 cells.
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.
authors.forename: Philip Y
authors.initials: PY
authors.lastname: Lam
authors.forename: Kam Ming
authors.initials: KM
authors.lastname: Ko
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D034242:Cyclooctanes / Q000494:pharmacology; D019610:Cytoprotection; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology*; D009574:Nitro Compounds / Q000633:toxicity*; D016716:PC12 Cells / Q000166:cytology / Q000378:metabolism; D011083:Polycyclic Compounds / Q000494:pharmacology*; D011422:Propionates / Q000633:toxicity*; D051381:Rats
chemical_list: D034242:Cyclooctanes; D017705:Lignans; D009574:Nitro Compounds; D011083:Polycyclic Compounds; D011422:Propionates; C015499:schizandrin B; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D005980:Glutathione Reductase; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione; C015392:3-nitropropionic acid