Molecular basis of vitamin E action: tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration.
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 alpha-tocotrienol, but not alpha-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 alpha-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 alpha-tocotrienol. In silico docking studies indicated that alpha-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 alpha-tocotrienol as a potent neuroprotective form of vitamin E.
Khanna
Savita
S
Laboratory of Molecular Medicine, Department of Surgery, Dorothy M. Davis Heart and lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Roy
Sashwati
S
Ryu
Hoon
H
Bahadduri
Praveen
P
Swaan
Peter W
PW
Ratan
Rajiv R
RR
Sen
Chandan K
CK
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001665:Binding Sites; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D024508:Tocotrienols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology* / Q000502:physiology*
D009498:Neurotoxins; D024508:Tocotrienols; D014810:Vitamin E; D018698:Glutamic Acid; C082032:tocotrienol, alpha; D001092:Arachidonate 12-Lipoxygenase; D005978:Glutathione