RT Journal Article
SR Electronic
T1 Ester Derivatives of Tournefolic Acid B Attenuate <em>N</em>-Methyl-<span class="sc">d</span>-aspartate-Mediated Excitotoxicity in Rat Cortical Neurons
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 950
OP 959
DO 10.1124/mol.105.018770
VO 69
IS 3
A1 Wang, Chuen-Neu
A1 Pan, Hsien-Chia
A1 Lin, Yun-Lian
A1 Chi, Chih-Wen
A1 Shiao, Young-Ji
YR 2006
UL http://molpharm.aspetjournals.org/content/69/3/950.abstract
AB The effects of tournefolic acid B (TAB) and two ester derivatives, TAB methyl ester (TABM) and TAB ethyl ester (TABE), on N-methyl-d-aspartate (NMDA)-mediated excitotoxicity and the underlying mechanisms were investigated. Treatment with 50 μM NMDA elicited neuronal death by 48.7 ± 5.1%, coinciding with the appearance of injured morphology. TABM (50 μM) attenuated the NMDA-induced cell death by 60.9 ± 19.7%, and to a lesser extent by TABE. The NMDA-mediated activation of calpain was not affected by TABM and TABE, as determined by the cleavage of α-spectrin. NMDA increased the activity of caspases 2, 3, 6, 8, and 9 and reached the maximum after 8-h treatment. TABM and TABE abrogated NMDA-induced activation of caspases 2, 3, 6, and 8 by approximately 80 to 90% and 50 to 60%, respectively, and to a higher extent for caspase 9. TABM and TABE also blocked the NMDA-mediated activation of caspase 12. Furthermore, TABM and TABE eliminated the NMDA-induced accumulation of superoxide anion (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{{\bar{{\cdot}}}}\) \end{document}). NMDA evoked significant depolarization of mitochondria, whereas TABM elicited a mild decrease of mitochondrial membrane potential as determined by tetramethylrhodamine methyl ester perchlorate. NMDA treatment induced elevation of Ca2+ levels in cytosol, endoplasmic reticulum (ER), and mitochondria. TABM (50 μM) significantly diminished the NMDA-induced elevation of Ca2+ levels in mitochondria and ER but not cytosol. Therefore, TABM decreased mitochondrial membrane potential and attenuated the NMDA-mediated Ca2+-loading in ER and mitochondria. These events subsequently eliminated the accumulation of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{{\bar{{\cdot}}}}\) \end{document} and blocked the activation of caspase cascade, thereby conferring their neuroprotective effects on NMDA-mediated excitotoxicity.