TableEdit

Chi, CW, Lin, YL, Wang, YH, Chen, CF, Wang, CN and Shiao, YJ (2008) 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. Eur. J. Pharmacol. 586:35-43

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.

PubMed Online version:10.1016/j.ejphar.2008.02.058

Amyloid beta-Peptides/antagonists & inhibitors; Amyloid beta-Peptides/toxicity; Animals; BH3 Interacting Domain Death Agonist Protein/physiology; Blotting, Western; Calcium/metabolism; Calcium/toxicity; Caspase 8/physiology; Cell Survival/drug effects; Cells, Cultured; Cerebral Cortex/cytology; Cerebral Cortex/drug effects; Cerebral Cortex/metabolism; Cytochromes c/physiology; Endoplasmic Reticulum/metabolism; Enzyme Activation/physiology; Heterocyclic Compounds, 3-Ring/pharmacology; Mitochondria/drug effects; Mitochondria/metabolism; Neurons/drug effects; Neurons/metabolism; Rats; Rats, Sprague-Dawley; Subcellular Fractions/metabolism; bcl-2 Homologous Antagonist-Killer Protein/metabolism