RRC ID |
38270
|
著者 |
Tanaka A, Hamada N, Fujita Y, Itoh T, Nozawa Y, Iinuma M, Ito M.
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タイトル |
A novel kavalactone derivative protects against H2O2-induced PC12 cell death via Nrf2/ARE activation.
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ジャーナル |
Bioorg Med Chem
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Abstract |
Oxidative stress is involved in the pathogenesis of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Natural kavalactones isolated from Piper methysticum (Piperaceae) are capable of activating the Nrf2/ARE (antioxidant response element) pathway and thus enhancing the expression of phase II antioxidant enzymes such as heme oxygenase-1 (HO-1). In an attempt to identify kavalactone derivatives that are more potent in Nrf2/ARE activation than natural compounds, we synthesized a series of chemically-modified kavalactones and studied their effects on the ARE enhancer activity in rat pheochromocytoma PC12 cells. Among 81 compounds tested, a kavalactone derivative, 2',6'-dichloro-5-methoxymethyl-5,6-dehydrokawain [(E)-6-(2',6'-dichlorostyryl)-4-methoxy-5-(methoxymethyl)-2H-pyran-2-one] (1), exhibited the strongest ARE enhancer activity. The ARE activation and HO-1 protein induction by the compound 1 were higher than those by natural kavalactones. The compound did not affect cell viability and induced expression of various phase II enzymes. Nuclear translocation of Nrf2 after treatment with 1 was preceded by phosphorylation of ERK1/2 and p38. The compound transiently increased intracellular ROS levels. Finally, pretreatment with the compound ameliorated H(2)O(2)-induced cell death, which was associated with increased expression of HO-1. These results suggest that the compound 1 protects against oxidative stress-induced neuronal cell death via a preconditioning effect on the Nrf2/ARE activation.
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巻・号 |
18(9)
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ページ |
3133-9
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公開日 |
2010-5-1
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DOI |
10.1016/j.bmc.2010.03.034
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PII |
S0968-0896(10)00238-5
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PMID |
20371185
|
MeSH |
Animals
Cell Death / drug effects
Hydrogen Peroxide*
Kava / chemistry*
Lactones / chemistry*
Lactones / pharmacology*
Molecular Structure
NF-E2-Related Factor 2 / drug effects*
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism
PC12 Cells
Rats
Response Elements / genetics
Signal Transduction
Transcriptional Activation / drug effects*
|
IF |
3.073
|
引用数 |
28
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WOS 分野
|
CHEMISTRY, MEDICINAL
CHEMISTRY, ORGANIC
BIOCHEMISTRY & MOLECULAR BIOLOGY
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リソース情報 |
ヒト・動物細胞 |
|