Abstract Title:

A novel kavalactone derivative protects against H2O2-induced PC12 cell death via Nrf2/ARE activation.

Abstract Source:

Bioorg Med Chem. 2010 May 1;18(9):3133-9. Epub 2010 Mar 20. PMID: 20371185

Abstract Author(s):

Arisa Tanaka, Nanako Hamada, Yasunori Fujita, Tomohiro Itoh, Yoshinori Nozawa, Munekazu Iinuma, Masafumi Ito

Article Affiliation:

Department of Longevity and Aging Research, Gifu International Institute of Biotechnology Naka-fudogaoka, Kakamigahara, Gifu 504-0838, Japan.


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.

Study Type : In Vitro Study

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