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Characterization of the potent neuroprotective properties of the natural vitamin E α‐tocotrienol
Author(s) -
Khanna Savita,
Roy Sashwati,
Parinandi Narasimham L.,
Maurer Mariah,
Sen Chandan K.
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04000.x
Subject(s) - tocotrienol , neuroprotection , neurotoxicity , vitamin e , antioxidant , oxidative stress , pharmacology , chemistry , biochemistry , linoleic acid , glutathione , biology , tocopherol , toxicity , fatty acid , enzyme , organic chemistry
The natural vitamin E tocotrienols possess properties not shared by tocopherols. Nanomolar α‐tocotrienol, not α‐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 α‐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 glutathionone GSSG/GSH, raised intracelular 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 α‐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, α‐tocotrienol functions as an antioxidant was verified in a model involving linoleic acid‐induced oxidative stress and cell death. Oral supplementation of α‐tocotrienol to humans results in a peak plasma concentration of 3 μ m . Thus, oral α‐tocotrienol may be neuroprotective by antioxidant‐independent as well as antioxidant‐dependent mechanisms.