Neuroprotective Properties of the Natural Vitamin E α-Tocotrienol

Abstract

Background and Purpose-The current work is based on our previous finding that in neuronal cells, nmol/L concentrations of ␣-tocotrienol (TCT), but not ␣-tocopherol (TCP), blocked glutamate-induced death by suppressing early activation of c-Src kinase and 12-lipoxygenase. Methods-The single neuron microinjection technique was used to compare the neuroprotective effects of TCT with that of the more widely known TCP. Stroke-dependent brain tissue damage was studied in 12-Lox-deficient mice and spontaneously hypertensive rats orally supplemented with TCT. Results-Subattomole quantity of TCT, but not TCP, protected neurons from glutamate challenge. Pharmacological as well as genetic approaches revealed that 12-Lox is rapidly tyrosine phosphorylated in the glutamate-challenged neuron and that this phosphorylation is catalyzed by c-Src. 12-Lox-deficient mice were more resistant to stroke-induced brain injury than their wild-type controls. Oral supplementation of TCT to spontaneously hypertensive rats led to increased TCT levels in the brain. TCT-supplemented rats showed more protection against stroke-induced injury compared with matched controls. Such protection was associated with lower c-Src activation and 12-Lox phosphorylation at the stroke site. Conclusion-The natural vitamin E, TCT, acts on key molecular checkpoints to protect against glutamate-and stroke-induced neurodegeneration. (Stroke. 2005;36:e144-e152.)

Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons

“…Both reduced GSH levels and increased ROS formation are established mechanisms that contribute to neuronal death in models of chronic and acute neurodegeneration. [19][20][21] Thus, the present finding in HT-22 cells showing a prominent role of 12/15-LOX for ROS formation in glutamate-induced cell death is relevant for mechanisms underlying neuronal injury and death in neurodegenerative diseases and after acute brain damage, such as trauma and stroke, where extracellular glutamate levels significantly increase after the respective injury. In addition, experiments in primary neurons also confirmed a major role for LOX-dependent mechanisms in glutamate-induced neuronal cell death in the presence of glutamate receptor ion channels.…”

Tocotrienol Vitamin E Protects against Preclinical Canine Ischemic Stroke by Inducing Arteriogenesis

“…Until this point, the current literature documents significant protective effects of stroke in vivo but explains it exclusively on the basis of TE's neuroprotective properties. a-Tocotrienol-specific mechanisms of neuroprotection depend on three key cytosolic targets involved in glutamate excitotoxicity and neurodegeneration: c-Src kinase, 12-lipoxygenase, and phospholipase A 2 (Khanna et al, 2005b;Khanna et al, 2010;Sen et al, 2000). Neuroprotectants alone, however, are thought to be insufficient in providing meaningful protection against stroke (Rogalewski et al, 2006).…”

“…To extract protein from the canine brain, S1 cortex and contralateral control tissue was homogenized on ice in lysis buffer (50 mmol/l Tris-HCL pH 7.6; 1.5 mmol/L NaCl; 0.5 mmol/L CaCl2; 0.01% Brij 35; 1% Triton X-100) and centrifuged at 41C for 15 minutes at 14,000 g. Protein expression of matrix metalloproteinase-2 (MMP2) in canine cortex was determined by western blot analysis as previously described (Khanna et al, 2005b) using MMP2 antibody (Enzo Life Sciences, Plymouth Meeting, PA, USA). Proteins were separated on 4% to 12% gels (Invitrogen, Carlsbad, CA, USA) by SDS-PAGE, transferred onto polyvinylidene difluoride membranes, and membranes were incubated with Tris-buffered saline (TBS) containing 5% milk for 12 to 18 hours at 41C with MMP2 antibody (1:400 dilution).…”

“…At nanomolar concentrations, a-tocotrienol (aTCT) but not a-tocopherol, is a potent neuroprotective agent (Khanna et al, 2005b). On a concentration basis, this represents the most potent of all the biological functions of the entire vitamin E family.…”

Effects of adding tocotrienol-tocopherol mixed fraction and vitamin C on inflammatory status in hypercholesterolaemic patients in the low coronary risk category

“…Tocotrienol has been proven to be a more potent antioxidant than tocopherols (Maniam et al, 2008). Furthermore, tocotrienol has been found to exert other effects outside of its antioxidant capabilities, such as cardioprotective (Das et al, 2007), neuroregenerative (Khanna et al, 2005) and anti-cancer properties (Aggarwal et al, 2010). It was also found to directly inhibit HMG-CoA reductase, the predominant enzyme in cholesterol metabolism (Khor and Ng, 2000).…”