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 2.881
Times Cited 22
Human and Animal Cells