title: Tournefolic acid B attenuates amyloid beta protein-mediated toxicity by abrogating the calcium overload in mitochondria and retarding the caspase 8-truncated Bid-cytochrome c pathway in rat cortical neurons.
abstract: The effect of tournefolic acid B (TAB) on amyloid beta protein-mediated neurotoxicity and the underlying mechanisms were investigated. Amyloid beta protein 25-35 elicited neuronal death as determined by calcein/ethidium homodimer-1 staining. 10 microM amyloid beta protein 25-35 caused cell death at a level of 41.5+/-3.8% by MTT reduction. 50 microM TAB attenuated the amyloid beta protein 25-35-induced cell death by 49.7+/-11.1%. TAB also abrogated amyloid beta protein-induced activation of caspases 8 and 9 by about 50-60%. Furthermore, TAB significantly diminished the amyloid beta protein 25-35-induced elevation of calcium level in mitochondria, whereas it did not affect the calcium level in cytosol or endoplasmic reticulum. TAB markedly retarded the amyloid beta protein-mediated release of cytochrome c from mitochondria. Amyloid beta protein 25-35 elevated mitochondrial truncated BH3 interacting domain death agonist (tBid) and decreased the level of B-cell leukemia/lymphoma-2alpha (Bcl-2alpha) in mitochondria. Moreover, amyloid beta protein induced a slight up-regulation of Bcl-2 agonist killer 1 (Bak) in cytosol. 50 microM TAB decreased the amyloid beta protein-induced elevation of mitochondrial tBid and the level of Bak, whereas it did not affect the amyloid beta protein-mediated decrease in mitochondrial Bcl-2alpha. Caspase 8 inhibitor significantly inhibited the amyloid beta protein-mediated increase in mitochondrial tBid and the release of cytochrome c. Therefore, TAB blocked the overload of calcium in mitochondria and impaired the amyloid beta protein-mediated activation of the caspase 8-tBid-cytochrome c pathway, thereby conferring its neuroprotective effects on amyloid beta protein-mediated neurotoxicity.
authors: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC.
authors: Chih-Wen
authors: CW
authors: Chi
authors: Yun-Lian
authors: YL
authors: Lin
authors: Ying-Hsiu
authors: YH
authors: Wang
authors: Chieh-Fu
authors: CF
authors: Chen
authors: Chuen-Neu
authors: CN
authors: Wang
authors: Young-Ji
authors: YJ
authors: Shiao
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000502:physiology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000633:toxicity*; D053181:Caspase 8 / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D045304:Cytochromes c / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D051023:BH3 Interacting Domain Death Agonist Protein; D006575:Heterocyclic Compounds, 3-Ring; D050998:bcl-2 Homologous Antagonist-Killer Protein; C460130:tournefolic acid B; D045304:Cytochromes c; D053181:Caspase 8; D002118:Calcium