Effects of vitamin E on stroke: a systematic review with meta-analysis and trial sequential analysis

Hong Chuan Loh, Renly Lim, Kai Wei Lee, Chin Yik Ooi, Deik Roy Chuan, Irene Looi, Yuen Kah Hay, Nurzalina Abdul Karim Khan

Stroke Vasc Neurol . 2020 Oct 27;svn-2020-000519. doi: 10.1136/svn-2020-00051

Abstract

There are several previous studies on the association of vitamin E with prevention of stroke but the findings remain controversial. We have conducted a systematic review, meta-analysis together with trial sequential analysis of randomised controlled trials to evaluate the effect of vitamin E supplementation versus placebo/no vitamin E on the risk reduction of total, fatal, non-fatal, haemorrhagic and ischaemic stroke. Relevant studies were identified by searching online databases through Medline, PubMed and Cochrane Central Register of Controlled Trials. A total of 18 studies with 148 016 participants were included in the analysis. There was no significant difference in the prevention of total stroke (RR (relative risk)=0.98, 95% CI 0.92-1.04, p=0.57), fatal stroke (RR=0.96, 95% CI 0.77-1.20, p=0.73) and non-fatal stroke (RR=0.96, 95% CI 0.88-1.05, p=0.35). Subgroup analyses were performed under each category (total stroke, fatal stroke and non-fatal stroke) and included the following subgroups (types of prevention, source and dosage of vitamin E and vitamin E alone vs control). The findings in all subgroup analyses were statistically insignificant. In stroke subtypes analysis, vitamin E showed significant risk reduction in ischaemic stroke (RR=0.92, 95% CI 0.85-0.99, p=0.04) but not in haemorrhagic stroke (RR=1.17, 95% CI 0.98-1.39, p=0.08). However, the trial sequential analysis demonstrated that more studies were needed to control random errors. Limitations of this study include the following: trials design may not have provided sufficient power to detect a change in stroke outcomes, participants may have had different lifestyles or health issues, there were a limited number of studies available for subgroup analysis, studies were mostly done in developed countries, and the total sample size for all included studies was insufficient to obtain a meaningful result from meta-analysis. In conclusion, there is still a lack of statistically significant evidence of the effects of vitamin E on the risk reduction of stroke. Nevertheless, vitamin E may offer some benefits in the prevention of ischaemic stroke and additional well-designed randomised controlled trials are needed to arrive at a definitive finding. PROSPERO registration number: CRD42020167827.

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Pretreatment with bisoprolol and vitamin E alone or in combination provides neuroprotection against cerebral ischemia/reperfusion injury in rats

Chiman Salehi, Monireh Seiiedy, Hamid Soraya, Farzaneh Fazli, Morteza Ghasemnejad-Berenji

Naunyn Schmiedebergs Arch Pharmacol . 2020 Oct 27. doi: 10.1007/s00210-020-02007-9. Online ahead of print.

Abstract

Global cerebral ischemia/reperfusion (I/R) induces selective neuronal injury in the hippocampus, leading to severe impairment in behavior, learning, and memory functions. This study aimed to evaluate the neuroprotective effects of bisoprolol (biso) and vitamin E (vit E) treatment alone or in combination on cerebral ischemia/reperfusion (I/R) injury. A total of 30 male rats were divided randomly into five groups (n = 6), sham, I/R, I/R + biso, I/R + vit E, and I/R + biso+vit E. Cerebral I/R group underwent global ischemia by bilateral common carotid artery occlusion for 20 min. Treatment groups received drugs once daily intraperitoneally for 7 days before the I/R induction. Locomotive and cognitive behaviors were utilized by open-field and Morris water maze tests. After behavioral testing, the brain was removed and processed to evaluate cerebral infarct size, histopathologic changes, myeloperoxidase (MPO) activity, and malondialdehyde (MDA) level. In I/R group tissue MDA and MPO levels and cerebral infarct size were significantly increased in comparison with the sham group. Furthermore, significant deficits were observed in locomotion and spatial memory after I/R. The areas of cerebral infarction, MPO, and MDA levels in biso, vit E, and combination group were significantly reduced compared with I/R group. Histopathological analysis demonstrated a significant reduction in leukocyte infiltration in all treated groups with the most profound reduction in the combination group. According to the behavioral tests, administration of biso and/or vit E protected locomotive ability and improved spatial memory after cerebral I/R. Our findings show that biso and vit E have beneficial effects against the I/R injury and due to their synergistic effects when administered in combination, may have a more pronounced protective effect on the cerebral I/R injury.

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Effect of Vitamin E on Cisplatin-induced Memory Impairment in Male Rats

Masoud Hosseinzadeh, Amir Alizadeh, Parnian Heydari, Marzieh Kafami, Mahmoud Hosseini, Farimah Beheshti, Narges Marefati, Moustafa Ghanbarabadi

Acta Neuropsychiatr . 2020 Oct 15;1-16. doi: 10.1017/neu.2020.34. Online ahead of print.

Abstract

Objective: Neurotoxicity is an adverse effect caused by cisplatin due to inflammation and oxidative stress in the central nervous system. The present study aimed to assess the effects of vitamin E injection on the learning and memory of rats with cisplatin-induced cognitive impairment.

Methods: Male rats were administered with cisplatin (2 mg/kg/7day ; i.p.) and/or vitamin E (200 mg/kg/7 day; i.p.) for one week, and the control group received saline solution. Spatial memory was evaluated using Morris water maze (MWM). In addition, the hippocampal concentrations of malondialdehyde (MDA), thiol, and superoxide dismutase (SOD) were measured using biochemical methods.

Results: According to the findings, cisplatin significantly increased the escape latency, while decreasing the time spent and traveled pathway in the target quadrant on the final trial day compared to the control group. Furthermore, pretreatment with vitamin E significantly reversed all the results in the spatial memory test. The biochemical data indicated that vitamin E could decrease MDA activity and increase thiol and SOD activity compared to the control group.

Conclusion: According to the results, vitamin E could improve cisplatin-induced memory impairment possibly through affecting the hippocampal oxidative status.

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Chemical Pathology of Homocysteine VIII. Effects of Tocotrienol, Geranylgeraniol, and Squalene on Thioretinaco Ozonide, Mitochondrial Permeability, and Oxidative Phosphorylation in Arteriosclerosis, Cancer, Neurodegeneration and Aging

Kilmer S McCully

Ann Clin Lab Sci . 2020 Sep;50(5):567-577.

Abstract

A century ago a fat-soluble vitamin from leafy vegetables, later named vitamin E, was discovered to enhance fertility in animals. Vitamin E consists of 8 isomers of tocopherols and tocotrienols, each containing chromanol groups that confer antioxidant properties and differ only in the 15-carbon saturated phytyl poly-isoprenoid side chain of tocopherols and the 15-carbon unsaturated farnesyl poly-isoprenoid side chain of tocotrienols. Although tocotrienol was first isolated from rubber plants in 1964, its importance in multiple disease processes was not recognized until two decades later, when the cholesterol-lowering and anti-cancer effects were first reported. Tocotrienol (T3) protects against radiation injury and mitochondrial dysfunction by preventing opening of the mitochondrial permeability transition pore, thereby inhibiting loss of the active site for oxidative phosphorylation, thioretinaco ozonide oxygen ATP, from mitochondria by complex formation with the active site, TR2CoO3O2NAD+H2PO4 T3. The preventive effects of tocotrienol on vascular disease, cancer, neurodegeneration and aging are attributed to its effects on cellular apoptosis and senescence. Geranylgeraniol is an important intermediate in the biosynthesis of cholesterol, and cholesterol auxotrophy of lymphoma cell lines and primary tumors is attributed to loss of squalene monooxygenase and accumulation of intracellular squalene. Geranylgeraniol and tocotrienol have synergistic inhibitory effects on growth and HMG CoA reductase activity, accompanied by reduction of membrane KRAS protein of cultured human prostate carcinoma cells. Since cholesterol inhibits opening of the mPTP pore of mitochondria, inhibition of cholesterol biosynthesis by these effects of tocotrienol and geranylgeraniol produces increased mitochondrial dysfunction and apoptosis from loss of the active site of oxidative phosphorylation from mitochondria.

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Effect of vitamin E on stroke-associated pneumonia

Hongwei Shen, Bingyan Zhan

J Int Med Res . 2020 Sep;48(9):300060520949657. doi: 10.1177/0300060520949657.

Abstract

Objective: To study the role of vitamin E in stroke-associated pneumonia.

Methods: We selected 183 patients with stroke-related pneumonia who were divided into different nutrition groups according to the Mini Nutritional Assessment score. Patients were then administered different doses of vitamin E.

Results: CD55 and CD47 levels in patients taking vitamin E across different nutrition score groups were better than those in patients who did not use vitamin E. The levels of CD55 and CD47 and the duration of hospitalization were better in the high-dose vitamin E group than in the low-dose vitamin E group.

Conclusion: Vitamin E may have an auxiliary therapeutic effect in patients with stroke-associated pneumonia.

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A first description of ataxia with vitamin E deficiency associated with MT-TG gene mutation

Marwa Maalej, Fatma Kammoun, Marwa Kharrat, Wafa Bouchaala, Marwa Ammar, Emna Mkaouar-Rebai, Chahnez Triki, Faiza Fakhfakh

Acta Neurol Belg . 2020 Sep 26. doi: 10.1007/s13760-020-01490-4. Online ahead of print.

Abstract

Ataxia with isolated vitamin E deficiency (AVED) is a rare autosomal recessive cerebellar ataxia disorder that is caused by a mutation in the alpha-tocopherol transfer protein gene TTPA, leading to a lower level of serum vitamin E. Although it is almost clinically similar to Friedreich’s ataxia, its devastating neurological features can be prevented with appropriate treatment. In this study, we present a patient who was initially diagnosed with Friedreich’s ataxia, but was later found to have AVED. Frataxin gene screening revealed the absence of GAA expansion in homozygous or heterozygous state. However, TTPAgene sequencing showed the presence of the c.744delA mutation, leading to a premature stop codon (p.E249fx). In addition, the result of mutational analysis of MT-DNA genes revealed the presence of several variants, including the m.10044A>G mutation in MT-TG gene. Here, we report for the first time the coexistence of both mitochondrial and nuclear genes mutations in AVED.

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Vitamin E is necessary for zebrafish nervous system development

Brian Head, Jane La Du, Robyn L Tanguay, Chrissa Kioussi, Maret G Traber

Sci Rep . 2020 Sep 21;10(1):15028. doi: 10.1038/s41598-020-71760-x.

Abstract

Vitamin E (VitE) deficiency results in embryonic lethality. Knockdown of the gene ttpa encoding for the VitE regulatory protein [α-tocopherol transfer protein (α-TTP)] in zebrafish embryos causes death within 24 h post-fertilization (hpf). To test the hypothesis that VitE, not just α-TTP, is necessary for nervous system development, adult 5D strain zebrafish, fed either VitE sufficient (E+) or deficient (E-) diets, were spawned to obtain E+ and E- embryos, which were subjected to RNA in situ hybridization and RT-qPCR. Ttpa was expressed ubiquitously in embryos up to 12 hpf. Early gastrulation (6 hpf) assessed by goosecoid expression was unaffected by VitE status. By 24 hpf, embryos expressed ttpa in brain ventricle borders, which showed abnormal closure in E- embryos. They also displayed disrupted patterns of paired box 2a (pax2a) and SRY-box transcription factor 10 (sox10) expression in the midbrain-hindbrain boundary, spinal cord and dorsal root ganglia. In E- embryos, the collagen sheath notochord markers (col2a1a and col9a2) appeared bent. Severe developmental errors in E- embryos were characterized by improper nervous system patterning of the usually carefully programmed transcriptional signals. Histological analysis also showed developmental defects in the formation of the fore-, mid- and hindbrain and somites of E- embryos at 24 hpf. Ttpa expression profile was not altered by the VitE status demonstrating that VitE itself, and not ttpa, is required for development of the brain and peripheral nervous system in this vertebrate embryo model.

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Brain α-Tocopherol Concentration and Stereoisomer Profile Alter Hippocampal Gene Expression in Weanling Mice

Justin S Rhodes, Catarina Rendeiro, Jonathan G Mun, Kristy Du, Pragya Thaman, Amanda Snyder, Heinrich Pinardo, Jenny Drnevich, Sriram Chandrasekaran, Chron-Si Lai, Karen J Schimpf, Matthew J Kuchan

J Nutr . 2020 Sep 16;nxaa249. doi: 10.1093/jn/nxaa249. Online ahead of print.

Abstract

Background: Alpha-tocopherol (αT), the bioactive constituent of vitamin E, is essential for fertility and neurological development. Synthetic αT (8 stereoisomers; all rac-αT) is added to infant formula at higher concentrations than natural αT (RRR-αT only) to adjust for bio-potency differences, but its effects on brain development are poorly understood.

Objectives: The objective was to determine the impact of bio-potency-adjusted dietary all rac-αT versus RRR-αT, fed to dams, on the hippocampal gene expression in weanling mice.

Methods: Male/female pairs of C57BL/6J mice were fed AIN 93-G containing RRR-αT (NAT) or all rac-αT (SYN) at 37.5 or 75 IU/kg (n = 10/group) throughout gestation and lactation. Male pups were euthanized at 21 days. Half the brain was evaluated for the αT concentration and stereoisomer distribution. The hippocampus was dissected from the other half, and RNA was extracted and sequenced. Milk αT was analyzed in separate dams.

Results: A total of 797 differentially expressed genes (DEGs) were identified in the hippocampi across the 4 dietary groups, at a false discovery rate of 10%. Comparing the NAT-37.5 group to the NAT-75 group or the SYN-37.5 group to the SYN-75 group, small differences in brain αT concentrations (10%; P < 0.05) led to subtle changes (<10%) in gene expression of 600 (NAT) or 487 genes (SYN), which were statistically significant. Marked differences in brain αT stereoisomer profiles (P < 0.0001) had a small effect on fewer genes (NAT-37.5 vs. SYN-37.5, 179; NAT-75 vs. SYN-75, 182). Most of the DEGs were involved in transcription regulation and synapse formation. A network analysis constructed around known vitamin E interacting proteins (VIPs) revealed a group of 32 DEGs between NAT-37.5 vs. SYN-37.5, explained by expression of the gene for the VIP, protein kinase C zeta (Pkcz).

Conclusions: In weanling mouse hippocampi, a network of genes involved in transcription regulation and synapse formation was differentially affected by dam diet αT concentration and source: all rac-αT or RRR-αT.

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Vitamin E reduces radiation injury of hippocampal neurons in mice by inhibiting ferroptosis

Chen Ren, Xuanzi Li, Shasha Du

Nan Fang Yi Ke Da Xue Xue Bao . 2020 Aug 30;40(8):1097-1102. doi: 10.12122/j.issn.1673-4254.2020.08.05.

Abstract

Objective: To explore the protective effect of vitamin E (VE) against radiation injury of hippocampal neurons in mice and explore the possible mechanism.

Methods: Cultured HT-22 and U251 cells with or without exposure to 8 Gy irradiation were treated with VE (200 μmol/L for 24 h), ferroptosis inhibitor (ferrostatin-1, 5 μmol/L for 24 h), apoptosis inhibitor (ZVAD-FMK, 2 μmol/L), or necroptosis inhibitor (100 μmol/L). MTT assay was used to evaluate the cell viability after the treatments, and reduced glutathione (GSH), malondialdehyde (MDA), lipid reactive oxygen species (lipid ROS), and intracellular iron ion levels were detected for assessment of ferroptosis. The mice exposed to 16 Gy irradiation with or without vitamin E (500 U/kg) treatment for 6 weeks were assessed for behavioral changes and cognitive functions using Morris water maze test.

Results: Treatment with VE significantly promoted the cell survival following irradiation in HT-22 cells (P &lt; 0.05) but not in U251 cells (P &gt; 0.05). Ferrostatin-1, but not ZVAD or the necroptosis inhibitor, promoted the survival of HT-22 cells following the irradiation. Exposure to irradiation significantly increased ferroptosis-related oxidative stress level in HT-22 cells, manifested by decreased GSH level and increased MDA, lipid ROS and intracellular iron ion levels (P &lt; 0.05); treatment with VE and ferrostatin-1 both obviously reversed radiation-induced ferroptosis-related oxidative stress in the cells (P &lt; 0.05). In Morris water maze test, the mice with radiation exposure showed obviously increased exploration time and distance (P &lt; 0.05), which were significantly decreased after treatment with VE (P &lt; 0.05).

Conclusions: Vitamin E reduces radiation injury by inhibiting ferroptosis in the hippocampal neurons in mice.

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Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex

Francisca A de Leeuw, Julie A Schneider, Sonal Agrawal, Sue E Leurgans, Martha Clare Morris

Alzheimers Dement (N Y) . 2020 Aug 24;6(1):e12021. doi: 10.1002/trc2.12021. eCollection 2020.

Abstract

Introduction: Higher brain tocopherol levels have been associated with lower levels of Alzheimer’s disease (AD) neuropathology; however, the underlying mechanisms are unclear.

Methods: We studied the relations of α- and γ-tocopherol brain levels to microglia density in 113 deceased participants from the Memory and Aging Project. We used linear regression analyses to examine associations between tocopherol levels and microglia densities in a basic model adjusted for age, sex, education, apolipoprotein E (APOE)ε4 genotype (any ε4 allele vs. none) , and post-mortem time interval, and a second model additionally adjusted for total amyloid load and neurofibrillary tangle severity.

Results: Higher α- and γ-tocopherol levels were associated with lower total and activated microglia density in cortical but not in subcortical brain regions. The association between cortical α-tocopherol and total microglia density remained statistically significant after adjusting for AD neuropathology.

Discussion: These results suggest that the relation between tocopherols and AD might be partly explained by the alleviating effects of tocopherols on microglia activation.

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