effectively lowered cholesterol levels. Thirty-two individuals with high cholesterol were ran- domly assigned to either 300 mg of mixed tocotrienols, or placebo capsules, for six months. The re- searchers report that “the serum total cholesterol and low densi- ty lipoprotein (LDL) cholesterol of the subjects in the tocotrien- ol supplementation group were decreased significantly…after 4 months of supplementation and the reduction persisted till the end of the 6-month study…more- over, there was a very impres- sive 22-fold increase in the total tocotrienol concentrations from baseline during supple- mentation compared to the placebo group, while the concentra- tion of tocopherol re- corded only a modest increase. On the other hand, the serum cholesterol, to- tal tocotrienol and tocopherol concentrations of subjects in the placebo group remained essen- tially unchanged.”31
The Cellular Pathways to Potent Protection
By what molecular magic do to- cotrienols protect the heart, brain and liver? Research is now eluci- dating many of the pathways.
In the brain, there are at least four antioxidant-independent pathways by which tocotrienols might uniquely prevent neu- rodegeneration. They do so by
regulating specific mediators of cell death.
Perhaps the most striking is the pathway regulated by the cSrc (short for “sarcoma”) gene. Scien- tists J. Michael Bishop and Har- old E. Varmus were awarded the 1989 Nobel Prize in Physiology or Medicine for discovering this gene. Its pathway regulates nor- mal and abnormal cell growth. Though this pathway has been studied intensively in cancer, it turns out that cSrc is also abun- dant in the brain. Overexpres- sion in this pathway can lead to
blockade of cSrc activity in mice provides cerebral protection fol- lowing stroke.” Alpha-toctotrie- nol powerfully inhibits expres- sion of this pathway.32
Thirty-two individuals with high cholesterol were randomly assigned to either 300 mg of mixed tocotrienols, or placebo capsules, for six months. The serum total cholesterol and low density lipoprotein (LDL) cholesterol of the subjects in the tocotrienol supplementation group decreased significantly.
glutamate-induced cell death. Too much glutamate, the most abundant neurotransmitter in the brain, is potentially deadly to the brain’s glial cells, corti- cal neurons, and other types of neurons.7,9,32
“cSrc is involved
in neurodegeneration in vivo,” states Sen. “Our pursuit for the neuroprotective mechanisms of tocotrienols led to the first evi- dence demonstrating that rapid cSrc activation plays a central role in executing neurodegen- eration. Consistently, it was demonstrated in a subsequent report that cSrc deficiency or
The second pathway is that of li- poxygenase, a fatty acid metab- olizing enzyme, which regulates a compound known as 12-Lox. Says Sen, “Our work led to the identification of 12-Lox as a key tocotrienol-sensitive mediator of neurodegeneration. 12-Lox represents a critical checkpoint in glutamate-induced neuro- degeneration.” Metabolites of 12-Lox are capable of causing cell death. Alpha-tocotrienol di- rectly interacts with this enzyme.7
Other pathways in- clude that of phos- pholipase, another enzyme related to lipid metabolism and
cell membrane viability, and the fourth involves MRP1 (also known as multi-drug resistance protein-1). All protect against neurodegeneration.7
For cholesterol, tocotrienols sup- press the activity of HMG-CoA reductase, the hepatic enzyme re- sponsible for cholesterol synthe- sis. And, according to a 2011 ge- nomics study on tocotrienols by Dipak Das and colleagues at the Cardiovascular Research Center at the University of Connecticut Health Center, tocotrienols reg- ulate several key, cholesterol-re- lated proteins. “The results of
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