title: A novel kavalactone derivative protects against H2O2-induced PC12 cell death via Nrf2/ARE activation.
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.
authors.affiliation: Department of Longevity and Aging Research, Gifu International Institute of Biotechnology Naka-fudogaoka, Kakamigahara, Gifu 504-0838, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Tanaka
authors.forename: Nanako
authors.initials: N
authors.lastname: Hamada
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fujita
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Itoh
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nozawa
authors.forename: Munekazu
authors.initials: M
authors.lastname: Iinuma
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D006861:Hydrogen Peroxide; D020901:Kava / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: C551968:2',6'-dichloro-5-methoxymethyl-5,6-dehydrokawain ((E)-6-(2',6'-dichlorostyryl)-4-methoxy-5-(methoxymethyl)-2H-pyran-2-one); D007783:Lactones; D051267:NF-E2-Related Factor 2; D006861:Hydrogen Peroxide