HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 44, 43508-43515, October 31, 2003

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 278/44/43508    most recent M307075200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khanna, S. Articles by Sen, C. K. Search for Related Content PubMed PubMed Citation Articles by Khanna, S. Articles by Sen, C. K. Social Bookmarking                      What's this?

Molecular Basis of Vitamin E Action

TOCOTRIENOL MODULATES 12-LIPOXYGENASE, A KEY MEDIATOR OF GLUTAMATE-INDUCED NEURODEGENERATION^*

Savita Khanna, Sashwati Roy, Hoon Ryu, Praveen Bahadduri¶, Peter W. Swaan¶, Rajiv R. Ratan, and Chandan K. Sen||

From the Laboratory of Molecular Medicine, Department of Surgery, and the ^¶Bioinformatics and Computational Biology Core Laboratory, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio 43210 and the Department of Neurology, Harvard Medical School, and the Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115

Vitamin E is a generic term for tocopherols and tocotrienols. This work is based on our striking evidence that, in neuronal cells, nanomolar concentrations of -tocotrienol, but not -tocopherol, block glutamate-induced death by suppressing early activation of c-Src kinase (Sen, C. K., Khanna, S., Roy, S., and Packer, L. (2000) J. Biol. Chem. 275, 13049–13055). This study on HT4 and immature primary cortical neurons suggests a central role of 12-lipoxygenase (12-LOX) in executing glutamate-induced neurodegeneration. BL15, an inhibitor of 12-LOX, prevented glutamate-induced neurotoxicity. Moreover, neurons isolated from 12-LOX-deficient mice were observed to be resistant to glutamate-induced death. In the presence of nanomolar -tocotrienol, neurons were resistant to glutamate-, homocysteine-, and L-buthionine sulfoximine-induced toxicity. Long-term time-lapse imaging studies revealed that neurons and their axo-dendritic network are fairly motile under standard culture conditions. Such motility was arrested in response to glutamate challenge. Tocotrienol-treated primary neurons maintained healthy growth and motility even in the presence of excess glutamate. The study of 12-LOX activity and metabolism revealed that this key mediator of glutamate-induced neurodegeneration is subject to control by the nutrient -tocotrienol. In silico docking studies indicated that -tocotrienol may hinder the access of arachidonic acid to the catalytic site of 12-LOX by binding to the opening of a solvent cavity close to the active site. These findings lend further support to -tocotrienol as a potent neuroprotective form of vitamin E.

View larger version (121K): [in this window] [in a new window]   FIG. 2. Imaging of glutamate-induced degeneration of rat primary cortical neurons and protection by -tocotrienol and BL15. After 24 h of seeding, cells were challenged with glutamate. Where indicated, neurons were pretreated with either -tocotrienol (250 nM) or BL15 (2.5 µM) for 5 min prior to glutamate treatment. a–d, neuronal class III -tubulin staining in the cultured neural network (for phase-contrast microscopy, see i–p). After 24 h of glutamate treatment, cells were fixed and stained. a, control; b, glutamate; c, -tocotrienol + glutamate; d, BL15 + glutamate. e–h, neurofilament staining in the cultured neural network (for phase-contrast microscopy, see i–p). e, control; f, glutamate; g, -tocotrienol + glutamate; h, BL15 + glutamate. i–p, live cell imaging of glutamate-treated neurons under standard (not glass coverslip) culture conditions. Phase-contrast images were collected once every 15 min for 18 h from 8 h after glutamate treatment. Frames illustrate time-dependent disintegration of the neural network. i, 8 h after glutamate treatment; j, 12 h; k, 16 h; l, 26 h. Glutamate-challenged neurons pretreated with -tocotrienol (250 nM) resisted degeneration and continued to grow. m, 28 h after glutamate treatment; n, 30 h; o, 32 h; p, 34 h. Two .avi video micrographs for i–l and m–p are included in the Supplemental Material. Magnification is x200.

Received for publication, July 2, 2003 , and in revised form, August 12, 2003.

^* This work was supported by NINDS Grant NS42617 from the National Institutes of Health (to C. K. S.). The modeling studies were additionally supported by NIDDK Grant 56631 from the National Institutes of Health (to P. W. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Video I (.avi file of 73 frames collected once every 15 min for 18 h; exported to .avi format at 300 ms/frame; total length of 21.9 s; compatible with Microsoft Windows Media Player) and Video II (.avi file of 33 frames collected once every 15 min for 18 h; exported to .avi format at 300 ms/frame; total length of 9.9 s; compatible with Microsoft Windows Media Player) of Fig. 2, i–l and m–p, respectively.

^|| To whom correspondence should be addressed: 512 Dorothy M. Davis Heart and Lung Research Inst., The Ohio State University Medical Center, 473 W. 12th Ave., Columbus, OH 43210. Tel.: 614-247-7786; Fax: 614-247-7818; E-mail: sen-1{at}medctr.osu.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				B. Langley, M. A. D'Annibale, K. Suh, I. Ayoub, A. Tolhurst, B. Bastan, L. Yang, B. Ko, M. Fisher, S. Cho, et al. Pulse Inhibition of Histone Deacetylases Induces Complete Resistance to Oxidative Death in Cortical Neurons without Toxicity and Reveals a Role for Cytoplasmic p21waf1/cip1 in Cell Cycle-Independent Neuroprotection J. Neurosci., January 2, 2008; 28(1): 163 - 176. [Abstract] [Full Text] [PDF]

				S. Khanna, S. Roy, H.-A Park, and C. K. Sen Regulation of c-Src Activity in Glutamate-induced Neurodegeneration J. Biol. Chem., August 10, 2007; 282(32): 23482 - 23490. [Abstract] [Full Text] [PDF]

				K. Nakagawa, A. Shibata, S. Yamashita, T. Tsuzuki, J. Kariya, S. Oikawa, and T. Miyazawa In Vivo Angiogenesis Is Suppressed by Unsaturated Vitamin E, Tocotrienol J. Nutr., August 1, 2007; 137(8): 1938 - 1943. [Abstract] [Full Text] [PDF]

				K. van Leyen, H. Y. Kim, S.-R. Lee, G. Jin, K. Arai, and E. H. Lo Baicalein and 12/15-Lipoxygenase in the Ischemic Brain Stroke, December 1, 2006; 37(12): 3014 - 3018. [Abstract] [Full Text] [PDF]

				Y. Zhang, H. Wang, J. Li, L. Dong, P. Xu, W. Chen, R. L. Neve, J. J. Volpe, and P. A. Rosenberg Intracellular Zinc Release and ERK Phosphorylation Are Required Upstream of 12-Lipoxygenase Activation in Peroxynitrite Toxicity to Mature Rat Oligodendrocytes J. Biol. Chem., April 7, 2006; 281(14): 9460 - 9470. [Abstract] [Full Text] [PDF]

				S. Khanna, S. Roy, A. Slivka, T. K.S. Craft, S. Chaki, C. Rink, M. A. Notestine, A. C. DeVries, N. L. Parinandi, and C. K. Sen Neuroprotective Properties of the Natural Vitamin E {alpha}-Tocotrienol Stroke, October 1, 2005; 36(10): e144 - e152. [Abstract] [Full Text] [PDF]

				S. Schaffer, W. E. Muller, and G. P. Eckert Tocotrienols: Constitutional Effects in Aging and Disease J. Nutr., February 1, 2005; 135(2): 151 - 154. [Abstract] [Full Text] [PDF]

				Y. Zhang, H. Wang, J. Li, D. A. Jimenez, E. S. Levitan, E. Aizenman, and P. A. Rosenberg Peroxynitrite-Induced Neuronal Apoptosis Is Mediated by Intracellular Zinc Release and 12-Lipoxygenase Activation J. Neurosci., November 24, 2004; 24(47): 10616 - 10627. [Abstract] [Full Text] [PDF]

				A. M. Vincent, J. W. Russell, P. Low, and E. L. Feldman Oxidative Stress in the Pathogenesis of Diabetic Neuropathy Endocr. Rev., August 1, 2004; 25(4): 612 - 628. [Abstract] [Full Text] [PDF]