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Molecular Pharmacology

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Research ArticleArticle

Ester Derivatives of Tournefolic Acid B Attenuate N-Methyl-d-aspartate-Mediated Excitotoxicity in Rat Cortical Neurons

Chuen-Neu Wang, Hsien-Chia Pan, Yun-Lian Lin, Chih-Wen Chi and Young-Ji Shiao
Molecular Pharmacology March 2006, 69 (3) 950-959; DOI: https://doi.org/10.1124/mol.105.018770
Chuen-Neu Wang
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Hsien-Chia Pan
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Yun-Lian Lin
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Chih-Wen Chi
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Young-Ji Shiao
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Abstract

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 (Math). 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 Math and blocked the activation of caspase cascade, thereby conferring their neuroprotective effects on NMDA-mediated excitotoxicity.

  • Received September 7, 2005.
  • Accepted December 19, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 69 (3)
Molecular Pharmacology
Vol. 69, Issue 3
1 Mar 2006
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Research ArticleArticle

Ester Derivatives of Tournefolic Acid B Attenuate N-Methyl-d-aspartate-Mediated Excitotoxicity in Rat Cortical Neurons

Chuen-Neu Wang, Hsien-Chia Pan, Yun-Lian Lin, Chih-Wen Chi and Young-Ji Shiao
Molecular Pharmacology March 1, 2006, 69 (3) 950-959; DOI: https://doi.org/10.1124/mol.105.018770

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Research ArticleArticle

Ester Derivatives of Tournefolic Acid B Attenuate N-Methyl-d-aspartate-Mediated Excitotoxicity in Rat Cortical Neurons

Chuen-Neu Wang, Hsien-Chia Pan, Yun-Lian Lin, Chih-Wen Chi and Young-Ji Shiao
Molecular Pharmacology March 1, 2006, 69 (3) 950-959; DOI: https://doi.org/10.1124/mol.105.018770
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