tocotrienols = neuroprotection

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1: J Neurochem. 2006 Sep;98(5):1474-86.

Characterization of the potent neuroprotective properties of the natural vitamin
E alpha-tocotrienol.

Khanna S, Roy S, Parinandi NL, Maurer M, Sen CK.

Laboratory of Molecular Medicine, Department of Surgery, Davis Heart and Lung
Research Institute, The Ohio State University Medical Center, Colombus, Ohio
43210, USA.

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.

PMID: 16923160 [PubMed - indexed for MEDLINE]

1: Ann N Y Acad Sci. 2004 Dec;1031:127-42.

Tocotrienol: the natural vitamin E to defend the nervous system?

Sen CK, Khanna S, Roy S.

Davis Heart & Lung Research Institute, 473 West 12th Avenue, The Ohio State
University Medical Center, Columbus, Ohio 43210, USA. sen-1@medctr.osu.edu

Vitamin E is essential for normal neurological function. It is the major
lipid-soluble, chain-breaking antioxidant in the body, protecting the integrity
of membranes by inhibiting lipid peroxidation. Mostly on the basis of symptoms
of primary vitamin E deficiency, it has been demonstrated that vitamin E has a
central role in maintaining neurological structure and function. Orally
supplemented vitamin E reaches the cerebrospinal fluid and brain. Vitamin E is a
generic term for all tocopherols and their derivatives having the biological
activity of RRR-alpha-tocopherol, the naturally occurring stereoisomer compounds
with vitamin E activity. In nature, eight substances have been found to have
vitamin E activity: alpha-, beta-, gamma- and delta-tocopherol; and alpha-,
beta-, gamma- and delta-tocotrienol. Often, the term vitamin E is synonymously
used with alpha-tocopherol. Tocotrienols, formerly known as zeta, , or
eta-tocopherols, are similar to tocopherols except that they have an isoprenoid
tail with three unsaturation points instead of a saturated phytyl tail. Although
tocopherols are predominantly found in corn, soybean, and olive oils,
tocotrienols are particularly rich in palm, rice bran, and barley oils.

Tocotrienols possess powerful antioxidant, anticancer, and cholesterol-lowering
properties. Recently, we have observed that alpha-tocotrienol is multi-fold more
potent than alpha-tocopherol in protecting HT4 and primary neuronal cells
against toxicity induced by glutamate as well as by a number of other toxins. At
nanomolar concentration, tocotrienol, but not tocopherol, completely protected
neurons by an antioxidant-independent mechanism. Our current work identifies two
major targets of tocotrienol in the neuron: c-Src kinase and 12-lipoxygenase.
Dietary supplementation studies have established that tocotrienol, fed orally,
does reach the brain. The current findings point towards tocotrienol as a potent
neuroprotective form of natural vitamin E.

PMID: 15753140 [PubMed - indexed for MEDLINE]


1: Neuropharmacology. 2004 Nov;47(6):904-15.

Alpha-tocotrienol provides the most potent neuroprotection among vitamin E
analogs on cultured striatal neurons.

Osakada F, Hashino A, Kume T, Katsuki H, Kaneko S, Akaike A.

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto
University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.

Oxidative stress and apoptosis play pivotal roles in the pathogenesis of
neurodegenerative diseases. We investigated the effects of vitamin E analogs on
oxidative stress and apoptosis using primary neuronal cultures of rat striatum.
A tocotrienol-rich fraction of edible oil derived from palm oil (Tocomin 50%),
which contains alpha-tocopherol, and alpha-, gamma- and delta-tocotrienols,
significantly inhibited hydrogen peroxide (H2O2)-induced neuronal death. Each of
the tocotrienols, purified from Tocomin 50% by high-performance liquid
chromatography, significantly attenuated H2O2-induced neurotoxicity, whereas
alpha-tocopherol did not. alpha-, gamma- and delta-Tocotrienols also provided
significant protection against the cytotoxicity of a superoxide donor, paraquat,
and nitric oxide donors, S-nitrosocysteine and 3-morpholinosydnonimine.
Moreover, tocotrienols blocked oxidative stress-mediated cell death with
apoptotic DNA fragmentation caused by an inhibitor of glutathione synthesis,
L-buthionine-[S,R]-sulfoximine. In addition, alpha-tocotrienol, but not gamma-
or delta-tocotrienol, prevented oxidative stress-independent apoptotic cell
death, DNA cleavage and nuclear morphological changes induced by a non-specific
protein kinase inhibitor, staurosporine. These findings suggest that
alpha-tocotrienol can exert anti-apoptotic neuroprotective action independently
of its antioxidant property. Among the vitamin E analogs examined,
alpha-tocotrienol exhibited the most potent neuroprotective actions in rat
striatal cultures.

PMID: 15527824 [PubMed - indexed for MEDLINE]