Distinct mechanisms underlie distinct polyphenol-induced neuroprotection.
Glutamate excitotoxicity is mediated by intracellular Ca(2+) overload, caspase-3 activation, and ROS generation. Here, we show that curcumin, tannic acid (TA) and (+)-catechin hydrate (CA) all inhibited glutamate-induced excitotoxicity. Curcumin inhibited PKC activity, and subsequent phosphorylation of NR1 of the NMDA receptor. As a result, glutamate-mediated Ca(2+) influx was reduced. TA attenuated glutamate-mediated Ca(2+) influx only when simultaneously administered, directly interfering with Ca(2+). Both curcumin and TA inhibited glutamate-induced caspase-3 activation. Although Ca(2+) influx was not attenuated by CA, caspase-3 was reduced by direct inhibition of the enzyme. All polyphenols reduced glutamate-induced generation of ROS.
Yazawa
Keiko
K
Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Kihara
Takeshi
T
Shen
Huilian
H
Shimmyo
Yoshiari
Y
Niidome
Tetsuhiro
T
Sugimoto
Hachiro
H
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002392:Catechin / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D059808:Polyphenols; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013634:Tannins / Q000737:chemistry / Q000494:pharmacology
D005419:Flavonoids; C409466:NR1 NMDA receptor; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010636:Phenols; D059808:Polyphenols; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D013634:Tannins; D018698:Glutamic Acid; D002392:Catechin; D011493:Protein Kinase C; D053148:Caspase 3; D003474:Curcumin