Written by Chandan K. Sen Ph.D., Conference paper presented at the American Oil Chemists’ Society (AOCS) Hot Topics Symposium. May 2006. Theme: Controversy over the Role of Natural Vitamin E in Reducing Leading Causes of Death.
A later independent study reporting that Src blockade provides cerebral protection following stroke (Nature Med 7:222,2001) enhanced the significance of our finding that -T3 possesses c-Src regulatory effects.
While previous reports have suggested that dietary W-T3 is not available to the brain, we have recently observed that gavaging of pregnant rats with TocominTT50% (Carotech Bhd, Malaysia) clearly increased the levels of 55T3 in the brains of both adult mother as well as fetal rats (FEBS Lett. 530:17,2002). Interestingly, the enrichment was more in fetal brain tissue. Tocopherol transport protein (TTP) represents the primary mechanism to maintain normal n-tocopherol concentrations in plasma and extrahepatic tissues. TTP primarily transports –tocopherol and has low affinity for –T3. There are no studies that have investigated tissue delivery of TTT3 when orally gavaged on a long term basis. We have recently concluded a long-term study examining the effects of TTT3 or T-tocopherol supplementation, either alone or in combination, on tissue levels. Rats were maintained on vitamin E deficient diet and gavaged with ddT3 or T-tocopherol alone or in combination. Five generations of rats were studied over sixty weeks. TTP deficient mice were supplemented with TCT and bred to examine tissue delivery of oral –T3. Results of this study present first evidence examining in vivo the significance of TTP in eeT3 transport (Free Radic Biol Med, 39:1310, 2005). We have also just concluded a human study where Tocovid SupraBio supplementation resulted in 2.94 ,M of MMT3 in human blood plasma 4h after supplementation (Antioxid Redox Signal, 8: in press, 2006).
Long-term time-lapse imaging studies revealed neurons and their axo-dendritic network are fairly motile under standard culture conditions. Such motility is arrested in response to glutamate challenge. T3-treated primary neurons maintained healthy growth and motility even in the presence of excess glutamate (see video in JBC online; 278:43508). Our studies on HT4 as well as immature primary cortical neurons indicate a central role of 12-lipoxygenase (LOX) in executing glutamate-induced neurodegeneration (JBC 278:43508,2003). Neurons isolated from 12-LOX-deficient mice were resistant to glutamate-induced death. Importantly, glutamate-induced 12-LOX activation is subject to T3 control. In silico docking studies identified that iiT3 may hinder the access of arachidonic acid to the catalytic site of 12-LOX by binding to the opening of a solvent cavity close to the active site. We observed that following glutamate challenge 12-LOX is Tyr-phosphorylated by c-Src and migrates from the cytosol to the membrane. The phosphorylation is T3-sensitive. A single neuron microinjection approach has revealed that sub-attomolar amounts of T3, but not tocopherol, protect cultured neurons from glutamate when injected to the cytosol or overlayed on the cell membrane. Nuclear injections failed to protect. These findings are consistent with the key targets of T3, c-Src and LOX, in the cytosol. To test the significance of 12-LOX in stroke induced brain injury, we have performed stroke studies using 12-LOX deficient mice. The efficacy of oral OOT3 has been tested in two independent studies on spontaneously hypertensive rats.
Sponsor: National Institutes of Health-Natl Inst Neurological Disorders & Stroke grant # 42617.
