Reference - Detail
| RRC ID | 38270 |
|---|---|
| Author | Tanaka A, Hamada N, Fujita Y, Itoh T, Nozawa Y, Iinuma M, Ito M. |
| Title | A novel kavalactone derivative protects against H2O2-induced PC12 cell death via Nrf2/ARE activation. |
| Journal | Bioorg Med Chem |
| 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. |
| Volume | 18(9) |
| Pages | 3133-9 |
| Published | 2010-5-1 |
| DOI | 10.1016/j.bmc.2010.03.034 |
| PII | S0968-0896(10)00238-5 |
| 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 |
| Times Cited | 28 |
| WOS Category | CHEMISTRY, MEDICINAL CHEMISTRY, ORGANIC BIOCHEMISTRY & MOLECULAR BIOLOGY |
| Altmetric score |
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| The most frequently cited source | |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | PC-12(RCB0009) |