Protective Effect of Tocotrienol on In Vitro and In Vivo Models of Parkinson’s Disease.

Matsura T.

J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S51-S53. doi: 10.3177/jnsv.65.S51.

Abstract

Parkinson’s disease (PD) is a common progressive neurodegenerative disease. It has been reported that oxidative stress contributes, at least in part, to its pathogenesis. Although dietary epidemiological studies suggest that sufficient intake of vitamin E may prevent the onset of PD, antioxidative therapy for PD with exogenous antioxidants involving α-tocopherol has not been successful in the clinical setting thus far. In recent years, the non-antioxidant activities of vitamin E have been given attention to. In the present study, to determine the antioxidant-independent cytoprotective activity of vitamin E, we investigated whether tocotrienols (T3s), another members of vitamin E family, exhibit the neuroprotective effect in cell and mouse models of PD independently of their antioxidant activities. Treatment with T3s, especially γ- and δ-T3s, exhibited cytoprotective effects via activation of PI3K/Akt signaling pathway in a cellular PD model. We also identified estrogen receptor (ER) β as an upstream mediator of PI3K/Akt signaling and demonstrated the direct binding of T3 to ERβ in vitro. Silencing expression of caveolin suppressed the cytoprotective effects of T3, indicating that caveola formation plays an important role in the cytoprotection by T3 via ERβ/PI3K/Akt signaling pathway. Thus it has been shown that T3 exerts cytoprotective function by a novel mechanism, which includes membrane ERβ/PI3K/Akt signaling via caveola formation as well as its antioxidant activity. Furthermore, we revealed that δ-T3 treatment relieved PD-related symptoms in PD model mice. These results suggest that T3 elicits the cytoprotective effects via ERβ/PI3K/Akt signaling pathway in cellular and murine PD models.

Hosseini M, Sarveazad A, Babahajian A, Baikpour M, Vaccaro AR, Chapman JR, Yousefifard M, Rahimi-Movaghar V

Nutr Rev. 2019 Dec 4. pii: nuz076. doi: 10.1093/nutrit/nuz076.

Abstract

CONTEXT:

Many animal studies have evaluated the role of vitamins in the recovery of motor function after spinal cord injury, but their results have been contradictory and no consensus has been reached.

OBJECTIVE:

This meta-analysis aimed to investigate the effects of vitamin C and vitamin E on recovery of motor function after spinal cord injury in animal models.

DATA SOURCES:

Two authors independently collected the records of relevant articles published in MEDLINE, Embase, Scopus, and Web of Science through November 2018.

STUDY SELECTION:

All studies conducted in animal models to evaluate the therapeutic effects of vitamin C or vitamin E or both on recovery of motor function after spinal cord injury were included. Studies that lacked a control group or a standard treatment, lacked an assessment of motor function, included genetically modified/engineered animals, included animals pretreated with vitamin C or vitamin E, or combined vitamin treatment with other methods, such as cell therapies, were excluded.

DATA EXTRACTION:

Data from 10 articles met the inclusion criteria for meta-analysis, conducted in accordance with PRISMA guidelines.

RESULTS:

Daily supplementation with vitamin C (P < 0.0001) and vitamin E (P < 0.0001) significantly improved the recovery of motor function in animals affected by spinal cord injury. Vitamin C supplementation is effective only when administered intraperitoneally (P < 0.0001). Concurrent supplementation with both vitamins does not show better efficacy than treatment with either one alone.

CONCLUSION:

Administration of vitamin C and vitamin E in animal models of spinal cord injury significantly improves the recovery of motor function.

Finno CJ, Peterson J, Kang M, Park S, Bordbari MH, Durbin-Johnson B, Settles M, Perez-Flores MC, Lee JH, Yamoah EN

iScience. 2019 Nov 22;21:720-735. doi: 10.1016/j.isci.2019.10.064.

Abstract

Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa^-/- mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa^-/- DRGNs showed marked upregulation of voltage-gated Ca²⁺ and K⁺ channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa^-/- DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation.

Ahmed M, Alzoubi KH, Khabour OF

Psychopharmacology (Berl). 2019 Nov 16. doi: 10.1007/s00213-019-05395-w.

Abstract

RATIONALE:

Post-traumatic stress disorder (PTSD) is a psychiatric disorder developed after an exposure to severe traumatic events. Patients with PTSD suffer from different symptoms including memory impairment. In addition, PTSD is associated with oxidative stress. Vitamin E, a fat-soluble vitamin, possesses cognition protective effects via its antioxidative properties.

OBJECTIVES:

To investigate the impact of vitamin E on memory impairment induced by PTSD in animals.

METHODS:

A rat model of PTSD-like behavior and the radial arm water maze (RAWM) for testing of learning and memory paradigm were used. Rats were divided into 4 groups: control, vitamin E, PTSD, and vitamin E + PTSD.

RESULTS:

In the learning phase, results showed no significant differences among experimental groups, indicating that PTSD-like behavior did not impair learning ability in rats. However, memory tests in the RAWM showed that PTSD-like animals had impairment in both short-term and long-term memories. Vitamin E, on the other hand, prevented this impairment of memory. With respect to oxidative stress, significant decreases were detected in reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, glutathione peroxidase (GPx) and catalase enzyme activities, global histone 3 acetylation, and brain derived neurotrophic factor (BDNF) levels in the PTSD-like animals group compared with other groups (P < 0.05). Vitamin E protected the reduction of these oxidative stress biomarkers, global histone 3 acetylation, and BDNF levels.

CONCLUSIONS:

Vitamin E prevented memory impairment associated with PTSD-like behavior in animals, probably via its antioxidative properties, and preservation of epigenetic changes induced in PTSD-like animals.

Ashley S, Bradburn S, Murgatroyd C

Nutr Neurosci. 2019 Oct 29:1-15. doi: 10.1080/1028415X.2019.1681066

Abstract

Objectives: Findings from observational studies and clinical trials on the associations between vitamin E and dementia remain controversial. Here we conducted a meta-analysis to determine the difference in blood tocopherols levels between patients with Alzheimer’s disease (AD) or age-related poor cognitive function and healthy controls.Methods: Standardised mean difference (SMD) and 95% confidence intervals (CIs) were calculated and entered into a random effects model. Study quality, heterogeneity and publication bias were also investigated.Results: Thirty-one articles were included in the meta-analysis, which included analyses for α-, β-, γ– and δ–tocopherols. These results indicated that individuals with AD or age-related cognitive deficits and mild cognitive impairment (MCI) had lower circulatory concentrations of α-tocophenol compared with healthy controls (AD: SMD = -0.97, 95% confidence interval [CI] = -1.27 to -0.68, Z = 6.45, P < 0.00001; age-related cognitive deficits and MCI: SMD = -0.72, 95% CI = -1.12 to -0.32, Z = -3., P < 0.0005). Levels of β-, γ– and δ-tocophenols did not significantly differ between groups of AD and age-related cognitive deficits compared to controls.Discussion: These results suggest that lower α–tocopherol levels have a strong association with AD and MCI supporting evidence for the role of diet and vitamin E in AD risk and age-related cognitive decline.

Zaulkffali AS, Md Razip NN, Syed Alwi SS, Abd Jalil A, Abd Mutalib MS, Gopalsamy B, Chang SK, Zainal Z, Ibrahim NN, Zakaria ZA, Khaza'ai H

Nutrients. 2019 Oct 19;11(10). pii: E2525. doi: 10.3390/nu11102525.

Abstract

This study investigated the effects of vitamins D and E on an insulin-resistant model and hypothesized that this treatment would reverse the effects of Alzheimer’s disease (AD) and improves insulin signalling. An insulin-resistant model was induced in SK-N-SH neuronal cells with a treatment of 250 nM insulin and re-challenged with 100 nM at two different incubation time (16 h and 24 h). The effects of vitamin D (10 and 20 ng/mL), vitamin E in the form of tocotrienol-rich fraction (TRF) (200 ng/mL) and the combination of vitamins D and E on insulin signalling markers (IR, PI3K, GLUT3, GLUT4, and p-AKT), glucose uptake and AD markers (GSK3β and TAU) were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The results demonstrated an improvement of the insulin signalling pathway upon treatment with vitamin D alone, with significant increases in IR, PI3K, GLUT3, GLUT4 expression levels, as well as AKT phosphorylation and glucose uptake, while GSK3β and TAU expression levels was decreased significantly. On the contrary, vitamin E alone, increased p–AKT, reduced the ROS as well as GSK3β and TAU but had no effect on the insulin signalling expression levels. The combination of vitamins D and E only showed significant increase in GLUT4, p-AKT, reduced ROS as well as GSK3β and TAU. Thus, the universal role of vitamin D, E alone and in combinations could be the potential nutritional agents in restoring the sensitivity of neuronal cells towards insulin and delaying the pathophysiological progression of AD.

Mahdinia R, Goudarzi I, Lashkarbolouki T, Salmani ME

Nutr Neurosci. 2019 Oct 14:1-15. doi: 10.1080/1028415X.2019.1674523.

Abstract

Objective: Alcohol exposure during pregnancy affects the developing fetus and causes a variety of physical and neurological abnormalities. Here we aim to study the effects of vitamin E on spatial learning and memory deficits and on changes in hippocampal brain-derived neurotrophic factor (BDNF) levels following perinatal ethanol exposure in rats. Method: Pregnant Wistar rats received ethanol (4 g/kg) and vitamin E (doses of 100, 200, and 400 mg/kg) on day 0 of gestation (GD) until weaning (28 days). On postnatal days (PND) 29, the performance of spatial learning and memory of rats were measured using the Morris water maze (MWM). The expression of BDNF protein levels in the hippocampus was assayed using BDNF ELISA kits. Results: Ethanol exposed group showed higher escape latency during training, reduced time spent in the target quadrant, higher escape location latency and average proximity in probe test. Vitamin E with doses of 100, 200 and 400 mg/kg significantly reduced escape latency during training. Also, vitamin E (400 mg/kg) significantly increased time spent in target quadrant, decreased escape location latency and average proximity in probe test. Maternal ethanol treatment significantly reduced the expression of BDNF protein in the hippocampus of offspring, whereas administration of vitamin E (400 mg/kg) significantly increased hippocampal BDNF in ethanol-treated rats. Discussion: Vitamin E administration dose-dependently ameliorate learning and memory deficits induced by perinatal ethanol exposure and increased hippocampal BDNF levels. BDNF may be implicated in the beneficial effects of vitamin E on learning and memory in the perinatal ethanol-exposed rat.

Abdul Rahman A, Mokhtar NM, Harun R, Jamal R, Wan Ngah WZ

J Physiol Biochem. 2019 Aug 14. doi: 10.1007/s13105-019-00699-z. [Epub ahead of print]

Abstract

Gamma-tocotrienol (GTT) and hydroxychavicol (HC) exhibit anticancer activity in glioma cancer cells, where the combination of GTT + HC was shown to be more effective than single agent. The aim of this study was to determine the effect of GTT + HC by measuring the cell cycle progression, migration, invasion, and colony formation of glioma cancer cells and elucidating the changes in gene expression mitigated by GTT + HC that are critical to the chemoprevention of glioma cell lines 1321N1 (grade II), SW1783 (grade III), and LN18 (grade IV) using high-throughput RNA sequencing (RNA-seq). Results of gene expression levels and alternative splicing transcripts were validated by qPCR. Exposure of glioma cancer cells to GTT + HC for 24 h promotes cell cycle arrest at G2M and S phases and inhibits cell migration, invasion, and colony formation of glioma cancer cells. The differential gene expression induced by GTT + HC clustered into response to endoplasmic reticulum (ER) stress, cell cycle regulations, apoptosis, cell migration/invasion, cell growth, and DNA repair. Subnetwork analysis of genes altered by GTT + HC revealed central genes, ATF4 and XBP1. The modulation of EIF2AK3, EDN1, and FOXM1 were unique to 1321N1, while CSF1, KLF4, and FGF2 were unique to SW1783. PLK2 and EIF3A gene expressions were only altered in LN18. Moreover, GTT + HC treatment dynamically altered transcripts and alternative splicing expression. GTT + HC showed therapeutic potential against glioma cancer as evident by the inhibition of cell cycle progression, migration, invasion, and colony formation of glioma cancer cells, as well as the changes in gene expression profiles with key targets in ER unfolded protein response pathway, apoptosis, cell cycle, and migration/invasion.

Gugliandolo A, Chiricosta L, Silvestro S, Bramanti P, Mazzon E

Brain Sci. 2019 Aug 10;9(8). pii: E196. doi: 10.3390/brainsci9080196.

Abstract

Alzheimer’s disease (AD) is the most common form of dementia worldwide. The hallmarks of AD are the extracellular amyloid plaques, which are formed by amyloid β (Aβ) aggregates derived from the processing of the amyloid precursor protein (APP), and the intraneuronal neurofibrillary tangles, which are formed by the hyperphosphorylated tau protein. The aim of this work was to study the effects of α-tocopherolin retinoic acid differentiated SH-SY5Y neuroblastoma cells exposed to Aβ_1-42 evaluating the transcriptional profile by next-generation sequencing. We observed that α-tocopherol was able to reduce the cytotoxicity induced by Aβ treatment, as demonstrated by Thiazolyl Blue Tetrazolium Bromide (MTT) assay. Moreover, the transcriptomic analysis evidenced that α-tocopherol treatment upregulated genes involved in the non-amyloidogenic processing of APP, while it downregulated the amyloidogenic pathway. Moreover, α-tocopherol modulated the expression of the genes involved in autophagy and the cell cycle, which are both known to be altered in AD. The treatment with α-tocopherolwas also able to reduce oxidative stress, restoring nuclear factor erythroid-derived 2-like 2 (Nrf2) and decreasing inducible nitric oxide synthase (iNOS) levels, as demonstrated by immunocytochemistry.

Matsuo K, Watanabe T, Takenaka A

Physiol Behav. 2019 Aug 1;207:64-72. doi: 10.1016/j.physbeh.2019.04.026. Epub 2019 May 4.

Abstract

It has been reported that the degree of anxiety-like behavior differs between inbred strains of mice, and that this phenomenon was linked to the expression levels of the oxidative stress-related genes glyoxalase 1 (Glo1) and glutathione reductase 1 (Gsr) in the brain. Therefore, we investigated whether antioxidative activity in the brain affects the Glo1 and Gsr mRNA expressions and strain-dependent anxiety-like behavior using mice fed different amounts of vitamin E. First, we measured brain Glo1 and Gsr mRNA levels and evaluated the anxiety-like behaviors presented by C57BL/6J (B6) and DBA/2C (D2) mice. We demonstrated that D2 mice presented both significantly elevated Glo1 and Gsr mRNA levels as well as more prominent anxiety-like behavior in elevated plus-maze and open field tests. Next, we fed mice from these two strains either a control, vitamin E-free, or vitamin E-supplemented diet for four weeks. Plasma, liver, and brain α-tocopherolconcentrations changed in a dose-dependent manner. However, neither brain Glo1 and Gsr mRNA levels nor anxiety-like behavior were affected by dietary vitamin E intake. These results demonstrated that while strain-dependent anxiety-like behavior in mice was related to oxidative stress-related gene expression, the regulatory mechanisms for these genes and anxiety-like behaviors were independent of antioxidative activity in the brain. Strain-dependent differences of the anxiety in mice are probably related to the anxiolytic effects of methylglyoxal, a substrate for Glo1 and Gsr.