Kaempferol derivatives prevent oxidative stress-induced cell death in a DJ-1-dependent manner.
DJ-1, a causative gene product of a familial form of Parkinson's disease (PD), PARK7, plays a role in anti-oxidative stress, and loss of its function is thought to result in the onset of PD. Superfluous oxidation of cysteine at amino acid 106 (C106) of DJ-1 renders DJ-1 inactive, and such oxidized DJ-1 was observed in patients with the sporadic form of PD. In this study, we examined the relationship between DJ-1 and compounds extracted from traditional Chinese medicines possessing anti-oxidant activity. Of the 12 compounds tested, 5 were found to specifically bind to the C106 region by using a quartz crystal microbalance. Although 4 compounds prevented rat PC12 and primary neuronal cells from undergoing H2O2-induced cell death, the protective activity of 2 compounds, kaempferol 3-O-beta-rutinoside and 6-hydroxykaempferol 3,6-di-O-beta-D-glucoside, was diminished in cells transfected with siRNA targeting DJ-1, indicating DJ-1-dependent reaction of these compounds. Furthermore, these compounds reduced the level of reactive oxygen species and restored tyrosine hydroxylase activity that had been induced and compromised, respectively, by treatment of cells with H2O2. The results suggest that these compounds are useful lead compounds for PD therapy.
Qu
Wei
W
Laboratory of Molecular Biolgy, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Fan
Li
L
Kim
Yun-chul
YC
Ishikawa
Shizuma
S
Iguchi-Ariga
Sanae M M
SM
Pu
Xiao-Ping
XP
Ariga
Hiroyoshi
H
D000818:Animals; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology*; D031178:Carthamus / Q000737:chemistry; D016923:Cell Death / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000008:administration & dosage; D044949:Kaempferols / Q000302:isolation & purification / Q000494:pharmacology*; D008516:Medicine, Chinese Traditional; D008869:Microtubule-Associated Proteins / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D000071617:Protein Deglycase DJ-1; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
D000975:Antioxidants; D044949:Kaempferols; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D014446:Tyrosine 3-Monooxygenase; C404267:PARK7 protein, rat; D000071617:Protein Deglycase DJ-1