Received for publication October 5, 2007.
Revised March 4, 2008.
Accepted for publication March 10, 2008.

Kavalactones protect neural cells against amyloid peptide-induced neurotoxicity via ERK1/2-dependent Nrf2-activation

Abstract

One hallmark of Alzheimer's disease is the accumulation of amyloid -peptide, which can initiate a cascade of oxidative events that may result in neuronal death. Since Nrf2 is the major regulator for a battery of genes encoding detoxifying and antioxidative enzymes via binding to the antioxidant response element (ARE), it is of great interest to find nontoxic activators of Nrf2 rendering neuronal cells more resistant to AP toxicity. Utilizing ARE-Luciferase assay and Western blot we give evidence that the kavalactones methysticin, kavain and yangonin activate Nrf2 time and dose dependently in neural PC12 and astroglial C6 cells and thereby upregulate cytoprotective genes. Viability and cytotoxicity assays demonstrate that Nrf2 activation is able to protect neural cells from A-(1-42) induced neurotoxicity. Downregulation of Nrf2 by shRNA as well as ERK1/2 inhibition abolishes cytoprotection. We further give evidence that kavalactones mediated Nrf2 activation is not depending on oxidative stress production. Our results demonstrate that kavalactones attenuate amyloid -peptide toxicity by inducing protective gene expression mediated by Nrf2 activation in vitro. These findings indicate that the use of purified kavalactones might be considered as an adjunct therapeutic strategy to combat neural demise in Alzheimer's Disease and other oxidative stress-related diseases.

Key words: MAP Kinase, Promoter analysis, Regulation of gene expression, Glutathione S-transferases, Phase II enzymes, Regulation - transcriptional, Oxidative stress/antioxidants, Radical intermediates, Reactive intermediates