Characterization of the potent neuroprotective properties of the natural vitamin E alpha-tocotrienol.
The natural vitamin E tocotrienols possess properties not shared by tocopherols. Nanomolar alpha-tocotrienol, not alpha-tocopherol, is potently neuroprotective. On a concentration basis, this finding represents the most potent of all biological functions exhibited by any natural vitamin E molecule. We sought to dissect the antioxidant-independent and -dependent neuroprotective properties of alpha-tocotrienol by using two different triggers of neurotoxicity, homocysteic acid (HCA) and linoleic acid. Both HCA and linoleic acid caused neurotoxicity with comparable features, such as increased ratio of oxidized to reduced glutathione GSSG/GSH, raised intracellular calcium concentration and compromised mitochondrial membrane potential. Mechanisms underlying HCA-induced neurodegeneration were comparable to those in the path implicated in glutamate-induced neurotoxicity. Inducible activation of c-Src and 12-lipoxygenase (12-Lox) represented early events in that pathway. Overexpression of active c-Src or 12-Lox sensitized cells to HCA-induced death. Nanomolar alpha-tocotrienol was protective. Knock-down of c-Src or 12-Lox attenuated HCA-induced neurotoxicity. Oxidative stress represented a late event in HCA-induced death. The observation that micromolar, but not nanomolar, alpha-tocotrienol functions as an antioxidant was verified in a model involving linoleic acid-induced oxidative stress and cell death. Oral supplementation of alpha-tocotrienol to humans results in a peak plasma concentration of 3 microm. Thus, oral alpha-tocotrienol may be neuroprotective by antioxidant-independent as well as antioxidant-dependent mechanisms.
Khanna
Savita
S
Laboratory of Molecular Medicine, Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Colombus, Ohio 43210, USA.
Roy
Sashwati
S
Parinandi
Narasimham L
NL
Maurer
Mariah
M
Sen
Chandan K
CK
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006710:Homocysteine / Q000031:analogs & derivatives / Q000633:toxicity; D006836:Hydro-Lyases / Q000378:metabolism; D019787:Linoleic Acid / Q000633:toxicity; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000494:pharmacology; D013997:Time Factors; D024508:Tocotrienols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D024508:Tocotrienols; D006710:Homocysteine; C007956:homocysteic acid; D014810:Vitamin E; D019787:Linoleic Acid; C082032:tocotrienol, alpha; D001092:Arachidonate 12-Lipoxygenase; D006836:Hydro-Lyases; C045581:lactate dehydratase; D005978:Glutathione; D002118:Calcium