Ester derivatives of tournefolic acid B attenuate N-methyl-D-aspartate-mediated excitotoxicity in rat cortical neurons.
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 microM NMDA elicited neuronal death by 48.7 +/- 5.1%, coinciding with the appearance of injured morphology. TABM (50 microM) 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 alpha-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 (O2-*). 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 microM) 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 O2-* and blocked the activation of caspase cascade, thereby conferring their neuroprotective effects on NMDA-mediated excitotoxicity.
Wang
Chuen-Neu
CN
National Research Institute of Chinese Medicine, No. 155-1. Sec. 2, LiNung St., Peitou, Taipei, Taiwan, Republic of China.
Pan
Hsien-Chia
HC
Lin
Yun-Lian
YL
Chi
Chih-Wen
CW
Shiao
Young-Ji
YJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013481:Superoxides / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D006575:Heterocyclic Compounds, 3-Ring; C460130:tournefolic acid B; C501215:tournefolic acid B methyl ester; D013481:Superoxides; D016202:N-Methylaspartate; D020169:Caspases; D002118:Calcium