Brain Health

Human Studies/ Cohort Studies

 

Article Study objective/ findings
Tocotrienol treatment in Familial Dysautonomia: open-label pilot study

Cheishvili, D, et.al (2016). J Mol Neurosci.

 

Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy, primarily presented in Ashkenazi Jews. Research findings show that tocotrienol treatment appears significantly beneficial by clinical evaluation for some FD patients in a few clinical parameters; however it was not significant by clinical measurements.

 

Clinical investigation of the protective effects of palm Vitamin E tocotrienols on brain white matter.

Gopalan Y.,et.al (2014). Stroke.

 

This study aims to evaluate the protective activity of mixed-tocotrienols in humans with white matter lesion (WML). Mixed-tocotrienol were found to attenuate the progression of WML.

 

 

Frataxin mRNA soforms in FRDA patients and normal subjects: effect of tocotrienol supplementation.

Abruzzo, P.M., et.al (2013). Biomed Res Int.

 

Low-dose tocotrienol supplementation effects on the expression of the three splice variant isoforms (FXN-1, FXN-2, and FXN-3) in mononuclear blood cells of FRDA patients and healthy subjects are evaluated. At a low dose of tocotrienol, the increase of FXN-3 expression appeared to be independent of PPARG expression. The data shows that it is possible to modulate the mRNA expression of the minor frataxin isoforms and that they may have a functional role.

 

Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults.

Mangialasche, F., et.al (2013). Exp Gerontol.

 

The association between serum levels of tocopherols and tocotrienols, markers of vitamin E oxidative/nitrosative damage (α-tocopherylquinone, 5-nitro-γ-tocopherol) and incidence of cognitive impairment in a population-based study is investigated. Elevated levels of tocopherol and tocotrienol forms are associated with reduced risk of cognitive impairment in older adults. Various vitamin E forms might play a role in cognitive impairment, and their evaluation can provide a more accurate measure of vitamin E status in humans.

 

Classification and prediction of clinical diagnosis of Alzheimer’s disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol.

Mangialasche, F., et.al (2013). J Intern Med.

 

This study evaluates the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms(four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects. The results suggest the potential role of nutritional biomarkers detected in plasma-tocopherols and tocotrienols-as indirect indicators of AD pathology, and the utility of a multimodality approach.

 

Tocopherols and tocotrienols plasma levels are associated with cognitive impairment

Mangialasche, F., et.al (2012). Neurobiol Aging.

 

Within the AddNeuroMed-Project, plasma tocopherols, tocotrienols, α-tocopherylquinone, and 5-nitro-γ-tocopherol were assessed in 168 AD cases, 166 MCI, and 187 cognitively normal (CN) people. Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD.

 

High plasma levels of vitamin E forms and reduced Alzheimer’s disease risk in advanced age.

Mangialasche, F., et.al (2010). J Alzheimers Dis.

The association between plasma levels of eight forms of vitamin E and incidence of Alzheimer’s disease (AD) among oldest-old individuals in a population-based setting was investigated. High plasma levels of vitamin E are associated with a reduced risk of AD in advanced age. The neuroprotective effect of vitamin E seems to be related to the combination of different forms, rather than to alpha-tocopherol alone, whose efficacy in interventions against AD is currently debated.

 

Can the therapeutic efficacy of tocotrienols in neurodegenerative gamilial dysautonomia patients be measured clinically?

Rubin, B.Y., et.al (2008). Antioxid Redox Signal.

 

Familial dysautonomia (FD) is an inherited, fatal, neurodegenerative disorder manifested by autonomic/hypertensive crises and cardiac instability. Based on these findings, it is hypothesized that tocotrienol therapy will improve the long-term clinical outlook and survival of individuals with FD.
Tocotrienols induce IKBKAP expression: A possible therapy for Familial Dysautonomia

Anderson, S.L., et.al (2003). Biochem Biophys Res Commun.

Familial dysautonomia (FD), a neurodegenerative genetic disorder primarily affecting individuals of Ashkenazi Jewish descent, is caused by mutations in the IKBKAP gene which encodes the IkappaB kinase complex-associated protein (IKAP). These findings suggest that in vivo supplementation with tocotrienols may elevate IKBKAP gene expression and in turn increase the amount of functional IKAP protein produced in FD patients.

In-vitro Studies

Study Study objectives/ findings
Gamma-tocotrienol acts as a BH3 mimetic to induce apoptosis in neuroblastoma SH-SY5Y cells.

Tan, J.K., et.al (2016). J Nutr Biochem.

Gamma-tocotrienol (γ-T3) can inhibit Bcl-2 to induce apoptosis. We demonstrate that γT3 induces cell death in human neuroblastoma SH-SY5Y cells by depolarising the mitochondrial membrane potential, enabling release of cytochrome c to the cytosol and increasing the activities of caspases-9 and -3. Γ-T3 mimics the action of BH3-only protein by binding to the hydrophobic groove of Bcl-2 and inducing apoptosis via the intrinsic pathway in a Bax- and caspase-9-dependent manner.

 

Tocotrienol Affects Oxidative Stress, Cholesterol Homeostasis and the Amyloidogenic Pathway in Neuroblastoma Cells: Consequences for Alzheimer’s Disease.

Grimm, M.O, et.al (2016). Int J Mol Sci.

The effect of alpha-tocotrienol on Alzheimer’s disease (AD)-relevant processes in neuronal cell lines is investigated. Tocotrienol inhibited Aβ degradation in neuro2a (N2a) cells.
Vitamin E, γ-tocotrienol, Protects Against Buthionine Sulfoximine-Induced Cell Death by Scavenging Free Radicals in SH-SY5Y Neuroblastoma Cells.

Tan, J.K., et.al (2016). Nutr Cancer.

The induction of reactive oxygen species (ROS) to selectively kill cancer cells is an important feature of radiotherapy and various chemotherapies. Depletion of glutathione can induce apoptosis in cancer cells or sensitize them to anticancer treatments intended to modulate ROS levels. In contrast, antioxidants protect cancer cells from oxidative stress-induced cell death by scavenging ROS. These results suggest that decreasing GSH levels by BSO increased ROS levels, leading to apoptosis in SH-SY5Y cells. γT3 attenuated the BSO-induced cell death by scavenging free radicals.

 

Synergistic cytotoxic effects of combined delta-tocotrienol and jerantinine B on human brain and colon cancers.

Abubaker, I.B., et.al (2016). J Ethnopharmacol

 

This study examines the mechanism of apoptosis induction in human glioblastoma (U87MG) and colorectal adenocarcinoma (HT-29) cancer cells by a novel indole alkaloid, jerantinine B isolated from T. corymbosa, δ-tocotrienol and the combined low-dose treatments of δ-tocotrienol with IC20 dose of jerantinine B. The present study demonstrated the mechanism for cytotoxic potency of δ-tocotrienol and jerantinine B against U87MG and HT-29 cells. Furthermore, combined low-dose treatments induced concurrent synergistic inhibition of cancer cell growth with concomitant dose reduction thus minimizing toxicity to normal cells and improving potency of δ-tocotrienol and jerantinine B.

 

Effect of vitamin E on 24(S)-hydroxycholesterol-induced necroptosis-like cell death and apoptosis.

Nakazawa, T., et.al (2016). J Steroid Biochem Mol Biol

 

24(S)-Hydroxycholesterol (24S-OHC) has diverse physiological and pathological functions. In particular, cytotoxic effects of 24S-OHC in neuronal cells are important in development of neurodegenerative diseases.  These results suggest that inhibition of 24S-OHC-induced cell death by α-Toc cannot be explained by its radical scavenging antioxidant activity. Esterification of 24S-OHC followed by lipid droplet (LD) formation due to acyl-CoA:cholesterol acyltransferase 1 (ACAT1) are key events in 24S-OHC-induced cell death in atRA-treated SH-SY5Y cells as demonstrated by inhibition of cell death by ACAT1 inhibitor. LD number was not changed by treatment with either α-Toc or α-Toc3. The different physical properties of α-Toc and α-Toc3 may account for their different inhibitory effects on 24S-OHC-induced cell death.

 

Cytoprotective Effect of Tocotrienol-Rich Fraction (TRF) and alpha-Tocopherol (α-T) Vitamin E Isoforms Against Glutamate-Induced Cell Death in Neuronal Cells.

Selvaraju, R., et.al (2014). Int J Nitam Nutr Res.

 

The potential of TRF and α-T as potent neuroprotective agents against glutamate-induced injury in neuronal SK-N-SH cells. Results show that vitamin E has potent antioxidant potential for protecting against glutamate injury and recovering glutamate-injured neuronal cells. Both TRF and α-T play key roles as anti-apoptotic agents with neuroprotective properties.
The Estrogen Receptor β-PI3K/Akt Pathway Mediates the Cytoprotective Effects of Tocotrienol in a Cellular Parkinson’s Disease Model

Nakaso, K., et.al (2014). Biochim Biophys Acta.

 

The signaling pathways that are induced during T3 (tocotrienol)-dependent cytoprotection of human neuroblastoma SH-SY5Y cells, as these cells are used to model certain elements of PD was investigated. This finding suggests that T3s and γT3/δT3 (gamma-, delta-tocotrienol) exhibit not only antioxidant effects but also a receptor signal-mediated protective action following ERβ/PI3K/Akt signaling. Furthermore, receptor-mediated caveola formation is an important event during the early steps following T3 treatment.

 

The neuroprotective effects of tocotrienol rich fraction (TRF) and alpha tocopherol (α-T) against glutamate injury in astrocytes

Selvaraju, T.R. et. al (2014). Bosn J Basic Med Sci.

 

The effects of vitamin E (TRF and α-T) in protecting astrocytes against glutamate injury were elucidated. Astrocytes induced with glutamate lead to significant cell death. However, glutamate mediated cytotoxicity was diminished via pre and post-supplementation of TRF and α-T. Hence, vitamin E acted as a potent antioxidant agent in recovering mitochondrial injury due to elevated oxidative stress, and enhanced better survivability upon glutamate toxicity.

 

Tocotrienol prevents AAPH-induced neurite degeneration in neuro2a cells.

Fukui, K, et. al (2013). Redox Rep.

Free radical-derived membrane injury is one possible mechanism for inducing neurite degeneration. Therefore, the potential neuroprotective effect of tocotrienols mediated through its antioxidant activity is examined. α-Tocotrienol may scavenge 2,2′-azobis(2-methylpropionamide) dihydrochloride (AAPH)-derived free radicals and alkoxyl radicals that are generated from AAPH-derived peroxyl radicals on cell membranes. Therefore, α-tocotrienol may have a neuroprotective effect mediated by its antioxidant activity.

 

Neuroprotective Effects of α-Tocotrienol on Kainic Acid-Induced Neurotoxicity in Organotypic Hippocampal Slice Cultures

Jung, N.Y., et.al (2013). Int J Mol Sci.

The effects of alpha-tocotrienol (α-T3) on kanaic acid (KA)-induced neuronal death using organotypic hippocampal slice culture (OHSC) and compared the neuroprotective effects of α-T3 and alpha-tocopherol (α-T). These data suggest that α-T and α-T3 treatment have protective effects on KA-induced cell death in OHSC. α-T3 treatment tended to be more effective than α-T treatment, even though there was no significant difference between α-T and α-T3 in co-treatment or post-treatment.

 

Loss of miR-29b following acute ischemic stroke contributes to neural cell death and infarct size.

Khanna, S., et.al (2013). J Cereb Blood Flow Metab.

 

This study investigates the significance of miR-29 in neurodegeneration associated with acute ischemic stroke. This work provides the first evidence demonstrating that loss of miR-29b at the infarct site is a key contributor to stroke lesion. Such loss is contributed by activity of the 12-lipoxygenase pathway providing maiden evidence linking arachidonic acid metabolism to miR-dependent mechanisms in stroke.

 

Tocotrienols prevent hydrogen peroxide-induced axon and dendrite degeneration in cerebellar granule cells

Fukui, K, et.al (2012). Free Radic Res.

Reactive oxygen species (ROS) attack several living tissues and increase the risk of development and progression of serious diseases. Treatment with each tocotrienol isoform prevented axonal and dendrite degeneration and induction of the abnormal band of the original band of collapsin response mediator protein (CRMP-2) in hydrogen peroxide-treated CGCs (cerebellar granule neurons). These results indicate that treatment with tocotrienols may therefore be neuroprotective in the presence of hydrogen peroxide by preventing changes to the CRMP-2 that occur before neuron death.

 

γ-Tocotrienol does not substantially protect DS (Down Syndrome) neurons from hydrogen peroxide-induced oxidative injury

Then, S-M., et.al (2012). Nutr Metab.

 

This study investigates the protective role of γ-tocotrienol (γ-T3) in DS neurons from hydrogen peroxide (H2O2)-induced oxidative stress. The pro-apoptosis tendency of γT3 was compared to α-tocopherol (αT) in non-stress condition as well. The result suggests that γ-T3 pre-treatment are not sufficient to protect DS neurons from H2O2-induced oxidative assault, instead induced the apoptosis process.

 

Natural Vitamin E α-Tocotrienol (α-T3) Protects Against Ischemic Stroke by Induction of Multidrug Resistance-Associated Protein 1

Park, Han-A., et.al. (2011). Stroke.

 

This work addresses a novel molecular mechanism by which α-T3 may be protective against stroke in vivo. (MRP1), a key mediator of GSSG efflux from neural cells, may therefore possess neuroprotective functions. This work recognizes MRP1 (multidrug resistance-associated protein 1) as a protective factor against stroke. Furthermore, findings of this study adds a new dimension to the current understanding of the molecular bases of α-T3 neuroprotection by identifying MRP1 as a α-T3 -sensitive target and by unveiling the general prospect that oral α-T3 may regulate microRNA expression in stroke-affected brain tissue.

 

Inhibitory Effects of Palm α-, γ- and δ-tocotrienol on lipopolysaccharide-induced nitric oxide production in BV2 microglia.

Tan, S.W., et.al (2011). Cell Immunol.

 

Anti-inflammatory actions of the vitamin E fragment tocotrienol have not been described for microglia. This study screens palm α-, γ- and δ-tocotrienol isoforms for their ability to limit nitric oxide (NO) production by BV2 microglia. Microglia were treated with varying doses of tocotrienols for 24 hours and stimulated with 1 μg/ml lipopolysaccharide (LPS). All tocotrienol isoforms reduced NO release by LPS-stimulated microglia, with 50 μM being the most potent tocotrienol dose. Of the isoforms tested, δ-tocotrienol lowered NO levels the most, reducing NO by approximately 50% at 48 hours post-LPS treatment. None of the tocotrienol doses tested affected microglia viability.

 

Hydrogen peroxide induces neurite degeneration: Prevention by tocotrienols

Fukui, K, et.al (2011). Cell Immunol.

Reactive oxygen species (ROS) may attack several types of tissues and chronic exposure to ROS may attenuate various biological functions and increase the risk of several types of serious disorders. These findings indicate that neurite beading is one of the early events of neuronal degeneration prior to induction of death of hydrogen peroxide-treated neurons. Treatment with tocotrienols may protect neurite function through its neuroprotective function.

 

Nanomolar vitamin E α-tocotrienol inhibits glutamate-induced activation of phospholipase A2 and causes neuroprotection

Khanna, S, et.al (2010). J Neurochem.

 

The hypothesis that phospholipase A2 (PLA2) activity is sensitive to glutamate and mobilizes arachidonic acid (AA), a substrate for 12-Lox. This work presents first evidence recognizing glutamate-induced changes in cPLA2 as a novel mechanism responsible for neuroprotection observed in response to nanomolar concentrations of tocotrienol.
Is Vitamin E Toxic to Neuron Cells?

Then, S.M., et.al (2009). Cell Mol Neurobiol.

 

This study elucidates whether protective effects shown by alpha-T and gamma-T3 in H(2)O(2)-induced neuron cultures have anti-apoptotic or pro-apoptotic tendency toward the initiation of neuronal apoptosis.  Low doses of gamma-T3 and alpha-T confer neuroprotection to H(2)O(2)-treated neurons via their antioxidant mechanism but gamma-T3 has stronger pro-apoptosis tendency than alpha-T by activating molecules involved in the neuronal apoptotic pathway in the absence of H(2)O(2).

 

Protection of Cerebellar Granule Cells by Tocopherols and Tocotrienols Against Methylmercury Toxicity

Shiciri, M., et.al (2007). Brain Res.

Excessive free radical formation has been implicated as one of the causative factors in neurotoxic damage associated with variety of metals, At micromolar concentration, tocotrienols, but not tocopherols, showed complete protection by an antioxidant mechanism. Similarly, tocopherols and tocotrienols showed a protective effect on CGCs (cerebellar granule cells) migration against MeHg (methylmercury)-toxicity. These results suggested that oxidative events may contribute to MeHg toxicity in isolated cerebellar granule neurons, and that tocotrienols are potent supplements for pharmacological protection of the developing brain exposed to MeHg.

 

Characterization of the potent neuroprotective properties of the natural vitamin E α-tocotrienol

Khanna, S., et.al (2006). J Neurochem.

The antioxidant-independent and –dependent neuroprotective properties of alpha-tocotrienol by using two different triggers of neurotoxicity, homocysteic acid (HCA) and linoleic acid were assessed. Oral alpha-tocotrienol may be neuroprotective by antioxidant-independent as well as antioxidant-mechanisms.

 

Tocotrienols Reverse IKAP and Monoamine Oxidase Deficiencies in Familial Dysautonomia.

Anderson, S.L., et.al (2005). Biochem Biophys Res Commun.

 

Familial dysautonomia (FD), a recessive neurodegenerative disease, is caused by mutations in the IKBKAP gene that result in the production of nonfunctional IKAP protein. Administration of tocotrienol to individuals with FD results in increased expression of both functional IKAP and MAO (monoamine oxidase) A transcripts in their peripheral blood cells. These findings provide new insight into the pathophysiology of FD and demonstrate the value of therapeutic approaches designed to elevate cellular levels of functional IKAP and MAO A.

 

Neuroprotective Properties of the Natural Vitamin E Alpha-tocotrienol

Khanna, S., et.al (2005). Stroke.

 

The study is based on previous finding that in neuronal cells, nmol/L concentrations of alpha-tocotrienol, but not alpha-tocopherol, blocked glutamate-induced death by suppressing early activation of c-Src kinase and 12-lipoxygenase. The natural vitamin E tocotrienol, acts on key molecular checkpoints to protect against glutamate- and stroke-induced neurodegeneration.

 

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

Sen C.K., et.al (2004). Ann N Y Acad Sci.

This study 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.

 

Alpha-tocotrienol Provides the Most Neuroprotection Among Vitamin E Analogs on Cultured Striatal Neurons

Osakada, F., et.al (2004). Neuropharmacology.

The effects of vitamin E analogs on oxidative stress and apoptosis using primary neuronal cultures of rat striatum. 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.
Molecular Basis of Vitamin E Action. Tocotrienol Modulates 12- Lipoxygenase, a Key Mediator of Glutamate-Induced Neurodegeneration

Khanna, S., et.al (2003). J Biol Chem.

The molecular mechanisms responsible for the potent neuroprotective property of trace amounts of tocotrienol has been characterized. Results from the current line of investigation identified the 12-lipoxygenase (LOX) pathway as being sensitive to tocotrienol. Findings lend further support to α-tocotrienol as a potent neuroprotective form of vitamin E.
Molecular aspects of alpha-tocotrienol antioxidant action and cell signaling

Parker, L., et.al (2001). J Nutr

Tocotrienols have beneficial effects in cardiovascular diseases both by inhibiting LDL oxidation and by down-regulating 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG CoA) reductase, a key enzyme of the mevalonate pathway. Important novel antiproliferative and neuroprotective effects of tocotrienols, which may be independent of their antioxidant activity, have also been described.

 

Molecular Basis of Vitamin E Action-Tocotrienol Potentially Inhibits Glutamate-Induced pp60c-src Kinase Activation and Death of HT4 Neuronal Cells

Sen, C.K., et.al (2000). J Bio Chem.

 

This study provides first evidence describing the molecular basis of tocotrienol action. At a concentration 4–10-fold lower than levels detected in plasma of supplemented humans, tocotrienol regulated unique signal transduction processes that were not sensitive to comparable concentrations of tocopherol.
Tocotrienols from palm oil as potent inhibitors of lipid peroxidation and protein oxidation in rat brain mitochondria

Kamat J.P. & Devasagayam, P.A. (1995). Neurosci Lett.

Tocotrienol-rich-fraction from palm oil is a natural antioxidant supplement capable of protecting the brain against oxidative damage.

Review Articles

Study Study objectives/findings
Tocotrienols, Health and Ageing: A Systematic Review.

Georgousopoulou, E.N., et.al (2017). Maturitas.

A systematic review of studies was undertaken to evaluate the potential effect of intake of tocotrienols or circulating levels of tocotrienols on parameters associated with successful ageing, specifically in relation to cognitive function, osteoporosis and DNA damage. Research in middle-aged and elderly humans suggests that tocotrienols have a potential beneficial anti-ageing action with respect to cognitive impairment and DNA damage. Clinical trials are required to elucidate these effects.

 

Do Tocotrienols Have Potentials as Neuroprotective Dietary Factors?

Frank J., et.al (2012). Ageing Res Rev

Tocotrienols (T3) belong to the family of vitamin E compounds (α-, β-, γ-, δ-tocopherols and -tocotrienols) and have unique biological properties that make them potential neuroprotective dietary factors.  Experiments in relevant animal models and randomized human intervention trials addressing the neuroprotection mediated by T3 are scarce and, thus, highly warranted.

 

Palm Oil–Derived Natural Vitamin E α-Tocotrienol in Brain Health and Disease

Chandan, K.S., et.al (2010). J Am Coll Nutr.

 

Palm oil derived vitamin E, α-tocotrienol from Elaeis guineensis represents the richest source of the lesser characterized. Palm oil–derived α-tocotrienol at nanomolar concentrations has been shown to attenuate both enzymatic and nonenzymatic mediators of AA metabolism and neurodegeneration. On a concentration basis, this represents the most potent of all biological functions exhibited by any natural vitamin E molecule. Despite such therapeutic potential, the scientific literature on tocotrienols accounts for roughly 1% of the total literature on vitamin E, thus warranting further investment and investigation.

 

Dietary Antioxidants as Potential Pharmacological Agents for Ischemic Stroke.

Cherubini, A., et.al (2008). Curr Med Chem.

Acute ischemic stroke is a leading cause of death and severe disability in industrialized countries and also in many developing countries. The most promising antioxidant compounds, i.e. dehydroascorbic acid, alpha-tocotrienol, gamma-tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke.

 

Tocotrienol: The Natural Vitamin E to Defend the Nervous System?

Sen, C.K., et. al (2004). Ann N Y Acad Sci.

Alpha-tocotrienol is multi-fold more potent than alpha-tocopherol in protecting HT4 and primary neuronal cells against toxicity induced by glutamate. 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.