nols can actually protect neuro- nal cells challenged with gluta- mate—a substance that in excess can be damaging to cells.6


The


c-Src, which I mentioned is one. Lipoxygenase, a fatty acid metab- olizing enzyme, is another. The third is phospholipase, another enzyme related to lipid metabo- lism, and the fourth, we finally reported in 2011, is MRP1 also known as multi-drug resistance protein-1. These are four targets or pathways that tocotrienols ad- dress, which may influence the neuroprotective properties, and not one works via an antioxidant mechanism. In fact, we showed that in cells damaged by gluta- mate, and in which there is a si- multaneous depletion of gluta- thione, the cell can be prevented from dying by tocotrienols, even though glutathione levels are not replenished by the mol- ecules. This means that even with inadequate glutathione, the cells can still be rescued if lipoxygenase is inhibited.7,8,9


Focus: Can you address the po- tency of tocotrienols? They seem effective in much lower amounts than tocopherols.


Sen: Yes. The molecular weight of something is often expressed in terms of molars, micromo- lars, nanomolars. Weight equal to molecular weight expressed in grams of a substance dissolved per liter is called molar strength.


That is a reference concentration. When using the term millimolar, you are talking about a thou- sandth of a molar. Then you get to micromolar, which is a mil- lionth of a molar. A billionth of a molar is a nanomolar. Tocoph- erols are often measured in the human blood in micromolars. You may find 25-50 micromolars of tocopherols in a blood sample. But tocotrienols are found at 1-5 micromolars in the blood, and in the neuronal cell a nanomolar concentration can prevent cell death. I do not know of any oth- er vitamin that shows biological function in the nanomolar range. It’s an incredibly tiny amount, and a fascinating finding. For instance, in one of our studies, we compared tocotrienols to a chemical inhibitor of lipoxygen- ase. Using this bonafide effective potent inhibitor of lipoxygenase requires about 2.5 micromolars. Yet the same enzyme is blocked by a hundred times lower dose of tocotrienols. That’s very striking.


Focus: When you look forward, what do you see ahead?


Sen: Taking a scientific solu- tion from the level of the mol- ecule to the human being is a very complex, interesting and rewarding exercise.


It involves


learning from failures and being cautious about successes. Unless we had taken all these years to understand tocotrienols and the


pathways by which they work, we would not be where we are today. I hope that eventually we will have results that will help people to void and recover from devastating neuronal and liver illness around the world. That would be the final payoff.


References:


1. Sen CK, Khanna S, Roy S, Packer L. Molecular ba- sis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp60(c-Src) kinase activation and death of HT4 neuronal cells. J Biol Chem. 2000 Apr 28;275(17):13049-55. PMID: 10777609


2. Khanna S, Roy S, Slivka A, Craft TK, Chaki S, Rink C, Notestine MA, DeVries AC, Parinandi NL, Sen CK. Neuroprotective properties of the natural vitamin E alpha-tocotrienol Stroke. 2005 Oct;36(10):2258-64. PMID: 16166580


3. Rink C, Christoforidis G, Abduljalil A, Kontzialis M, Bergdall V, Roy S, Khanna S, Slivka A, Knopp M, Sen CK. Minimally invasive neuroradiologic model of preclinical transient middle cerebral artery occlu- sion in canines. Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14100-5. PMID: 18779582


doi: 10.1073/pnas.0806678105.


4. Rink C, Christoforidis G, Khanna S, Peterson L, Patel Y, Khanna S, Abduljalil A, Irfanoglu O, Machi- raju R, Bergdall VK, Sen CK. Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis. J Cereb Blood Flow Metab. 2011 Nov;31(11):2218-30. doi: 10.1038/jcbfm.2011.85. PMID: 21673716


5. Patel V, Rink C, Gordillo GM, Khanna S, Gnyawa- li U, Roy S, Shneker B, Ganesh K, Phillips G, More JL, Sarkar A, Kirkpatrick R, Elkhammas EA, Klatte E, Miller M, Firstenberg MS, Chiocca EA, Nesaretnam K, Sen CK. Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients. J Nutr. 2012 Mar;142(3):513-9. doi: 10.3945/jn.111.151902. Epub 2012 Feb 1. PMID: 22298568


6. Sen CK, et al. Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp60(c-Src) kinase activation and death of HT4 neu- ronal cells. J Biol Chem. (2000)


7. Khanna S, Roy S, Park HA, Sen CK. Regulation of c-Src activity in glutamate-induced neurodegen- eration. J Biol Chem. 2007 Aug 10;282(32):23482-90. PMID: 17569670


8. Sen CK, et al. Tocotrienol: the natural vitamin E to defend the nervous system? Ann N Y Acad Sci. 2004 Dec;1031:127-42.)


9. Patel V, Rink C, Khanna S, Sen CK Tocotrienols: the lesser known form of natural vitamin E. Indian J Exp Biol. 2011 Oct;49(10):732-8. Review. PMID: 22013739


Focus April 2013


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