Three distinct neuroprotective functions of myricetin against glutamate-induced neuronal cell death: involvement of direct inhibition of caspase-3.
The excitatory neurotransmitter glutamate can accumulate in the brain and is thought to be involved in the etiology of many neurodegenerative disorders, including ischemia and Alzheimer disease. Therefore, it is important to search for compounds that reduce glutamate neurotoxicity. This glutamate-mediated excitotoxicity is caused by intracellular Ca2+ overload via the N-methyl-D-aspartate receptor NMDAR), reactive oxygen species (ROS) generation, and caspase-3 activation. Here we show that the natural flavonoid myricetin inhibited glutamate-induced excitotoxicity and protected neurons by multiple, distinct pathways. First, myricetin affected modulation of the NMDAR by phosphorylation, causing a subsequent reduction in glutamate-induced intracellular Ca2+ overload. Second, myricetin inhibited the ROS production caused by glutamate. Finally, glutamate-induced activation of caspase-3 was reduced by myricetin treatment. Moreover, myricetin directly interacted with the active site of caspase-3 via three hydrogen bonds and inhibited its activity. We conclude that myricetin inhibited glutamate-induced neuronal toxicity by multiple biochemical pathways. These results show that myricetin is a potent antineurodegenerative compound and may contribute to the discovery of a drug with which to combat neurodegeneration.
Shimmyo
Yoshiari
Y
Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Kihara
Takeshi
T
Akaike
Akinori
A
Niidome
Tetsuhiro
T
Sugimoto
Hachiro
H
D000818:Animals; D053148:Caspase 3 / Q000502:physiology; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity*; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018696:Neuroprotective Agents; D018698:Glutamic Acid; C040015:myricetin; D053148:Caspase 3