Tournefolic acid B methyl ester attenuates glutamate-induced toxicity by blockade of ROS accumulation and abrogating the activation of caspases and JNK in rat cortical neurons.
The effects of nine polyphenolic compounds on glutamate-mediated toxicity were investigated. The underlying mechanisms by which a polyphenolic compound confers its effect were also elucidated. Treatment of cortical neurons with 50 microm glutamate for 24 h decreased cell viability by 45.8 +/- 7.9%, and 50 microm of tournefolic acid B methyl ester attenuated glutamate-induced cell death by 46.8 +/- 17.8%. Glutamate increased the activity of caspase 35.2-fold, and to a similar extent for caspase 2, 6, 8 and 9. Tournefolic acid B methyl ester abrogated glutamate-induced activation of caspase 2, 3, 6 and 9 by about 70%, and to a lesser extent for caspase 8. Treatment with glutamate for 1 h elevated reactive oxygen species (ROS) by 208.3 +/- 21.3%. Tournefolic acid B methyl ester eliminated the glutamate-induced accumulation of ROS. Glutamate increased the phosphorylation of p54-c-jun N-terminal kinase (JNK) concomitantly with activation of the endogenous antioxidant defense system. Tournefolic acid B methyl ester at 50 microm diminished the activity of p54-JNK in control and glutamate-treated cells, coinciding with the abolishment of the glutamate-triggered antioxidant defense system. Therefore, tournefolic acid B methyl ester blocked the activation of the caspase cascade, eliminated ROS accumulation and abrogated the activation of JNK, thereby conferring a neuroprotective effect on glutamate-mediated neurotoxicity.
Chi
Chih-Wen
CW
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
Wang
Chuen-Neu
CN
Lin
Yun-Lian
YL
Chen
Chieh-Fu
CF
Shiao
Young-Ji
YJ
D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004365:Drugs, Chinese Herbal / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D059808:Polyphenols; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism
D061945:Caspase Inhibitors; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D006575:Heterocyclic Compounds, 3-Ring; D010636:Phenols; D059808:Polyphenols; D017382:Reactive Oxygen Species; C501215:tournefolic acid B methyl ester; D018698:Glutamic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D005978:Glutathione