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ToxSci Advance Access originally published online on September 18, 2009
Toxicological Sciences 2009 112(2):435-449; doi:10.1093/toxsci/kfp230
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Metallothionein-III Provides Neuronal Protection through Activation of Nuclear Factor-{kappa}B via the TrkA/Phosphatidylinositol-3 kinase/Akt Signaling Pathway

Hyung Gyun Kim*,1, Yong Pil Hwang*,1, Eun Hee Han*, Chul Yung Choi{dagger}, Chang-Yeol Yeo{ddagger}, Jin Young Kim*, Kwang Youl Lee§,2 and Hye Gwang Jeong*,¶,2

* Department of Pharmacy and Research Center for Proteineous Materials, College of Pharmacy, Chosun University, Gwangju, South Korea {dagger} Department of Food Science, College of Public Health and Natural Science, Korea International University, Jinju, South Korea {ddagger} Department of Life Science, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, South Korea § Department of Pharmacy, College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju, South Korea Department of Pharmacy, College of Pharmacy, Chungnam National University, Daejeon, South Korea

2 To whom correspondence should be addressed: Department of Pharmacy, College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea. Fax: +82-42-825-4939. E-mail: hgjeong{at}cnu.ac.kr.

Received June 26, 2009; accepted September 15, 2009


  Abstract

Metallothionein (MT)-III is associated with resistance to neuronal injury. However, the underlying mechanism for its effects is unclear. The present study investigated the mechanisms of MT-III protection of neuronal cells from hypoxia or DNA damage–induced cell death. MT-III reduced the hydrogen peroxide– or DNA damage–induced effects on neuronal cells, including the cell death, the activation of caspase-3 and -9, and the release of mitochondrial cytochrome c to the cytoplasm in a dose-dependent manner. MT-III also increased the activation of Akt, the phosphorylation and degradation of I{kappa}B, the nuclear translocation/accumulation and the transcriptional activity of nuclear factor-{kappa}B (NF-{kappa}B) in neuronal cells in a dose-dependent manner. The MT-III–induced antiapoptotic effects and increase in NF-{kappa}B activity were blocked by specific inhibitors of TrkA, phosphatidylinositol-3 kinase (PI3K), Akt, or NF-{kappa}B, indicating that MT-III provides neuronal protection by activating NF-{kappa}B through the TrkA/PI3K/Akt signaling pathway.

Key Words: metallothionein-III; neuronal protection; NF-{kappa}B; TrkA; Akt.

1 These authors contributed equally to this study.


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