Vitamin E reduces inflammation and improves cognitive disorder and vascular endothelial functions in patients with leukoaraiosis

Yan Wang, Guoce Li, Jianping Lv, Yingwen Zhou, Hongxia Ma

Int J Neurosci . 2022 Jun 2;1-9. doi: 10.1080/00207454.2022.2079505. Online ahead of print.


Background: Leukoaraiosis (LA) is a disease manifested by demyelination and gliosis in white matter, mainly caused by cerebrovascular diseases. LA is closely related to the expression level of inflammatory factors, oxidative stress, and vascular endothelial dysfunction in patients. Vitamin E may play antioxidant and anti-inflammatory roles in various diseases. We aimed to explore the effects of vitamin E on the patients with LA.

Methods: A total of 160 patients with LA were recruited in this research. Matrix metalloproteinase-9 (MMP-9), MMP-2, C-reactive protein (CRP), complement 3 (C3), C4, nitric oxide (NO), and endothelin (ET) levels were evaluated by ELISA. The Mini-Mental State Examination (MMSE) was used for cognitive impairment assessment. Superoxide dismutase (SOD) and malondialdehyde (MDA) concentrations were analyzed by commercial kits.

Results: The levels of CRP, C3, and C4 significantly decreased in the serum of LA patients after the administration of vitamin E. The levels of MMP-2 and MPP-9 showed a significant decrease in the administered group. Vitamin E significantly inhibited the expression of MDA, while significantly upregulated the expression of SOD. Significant increase in NO production and significant downregulation of ET expression occurred in vitamin E groups. MMSE score was significantly increased by vitamin E.

Conclusion: In conclusion, vitamin E showed effects on the alleviation of inflammatory response, oxidative stress, endothelial damage, and cognitive dysfunction. Thus, vitamin E could be a potential drug for the clinical treatment of LA patients.

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Alpha- and Gamma-Tocopherol Modulates the Amyloidogenic Pathway of Amyloid Precursor Protein in an in vitro Model of Alzheimer’s Disease: A Transcriptional Study

Aslina Pahrudin Arrozi, Siti Nur Syazwani Shukri, Nuraqila Mohd Murshid, Ahmad Baihaqi Ahmad Shahzalli, Wan Zurinah Wan Ngah, Hanafi Ahmad Damanhuri, Suzana Makpol

Front Cell Neurosci . 2022 May 5;16:846459. doi: 10.3389/fncel.2022.846459. eCollection 2022.


The amyloid precursor protein (APP) processing pathway was altered in Alzheimer’s disease (AD) and contributed to abnormal amyloid-beta (Aβ) production, which forms insoluble interneuron protein aggregates known as amyloid plaques in the brain. Targeting the APP processing pathway is still fundamental for AD modifying therapy. Extensive research has evaluated the protective effects of vitamin E as an antioxidant and as a signaling molecule. The present study aimed to investigate the modulatory effects of different tocopherol isomers on the expression of genes involved in regulating the APP processing pathway in vitro. The screening for the effective tocopherol isomers in reducing APP expression and Aβ-42 was carried out in SH-SY5Y stably overexpressed APP Swedish. Subsequently, quantitative one-step real-time PCR was performed to determine the modulatory effects of selected tocopherol isomers on the expression of genes in SH-SY5Y stably overexpressed three different types of APP (wild-type, APP Swedish, and APP Swedish/Indiana). Our results showed that all tocopherol isomers, especially at higher concentrations (80-100 μM), significantly increased (p < 0.05) the cell viability in all cells group, but only α-tocopherol (ATF) and γ-tocopherol (GTF) significantly decreased (p < 0.05) the APP mRNA level without statistically significant APP protein level, accompanied with a reduced significance (p < 0.05) on the level of Aβ-42 in SH-SY5Y APP Swedish. On the other hand, β- and δ-tocopherol (BTF and DTF) showed no effects on the level of APP expression and Aβ-42. Subsequent results demonstrated that ATF and GTF significantly decreased (p < 0.05) the expression of gene beta-site APP cleaving enzyme (BACE1), APH1B, and Nicastrin (NCSTN), but significantly increased (p < 0.05) the expression of Sirtuin 1 (SIRT1) in SH-SY5Y stably expressed the mutant APP form. These findings suggested that ATF and GTF could modulate altered pathways and may help ameliorate the burden of amyloid load in AD.

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The Protective Effects of Combination Vitamin E and Swimming Exercise on Memory Impairment Induced by Exposure to Waterpipe Smoke

Karem H Alzoubi, Abdulsalam M Halboup, Omar F Khabour, Mahmoud M Alomari

CNS Neurol Disord Drug Targets . 2022 Mar 18. doi: 10.2174/1871527321666220318113635. Online ahead of print.


Background: Waterpipe smoking (WP) exposure has a negative health impact including memory deficit which was attributed to elevation of oxidative stress. Vitamin E (VitE) or swimming exercise have protective effects that prevent memory impairment. In the current study, the modulation of WP-induced memory impairment by the combined effect of VitE and swimming exercise (SE) was investigated.

Method: Animals were exposed to WP one hour/day, five days per week for four weeks. Simultaneously, VitE (100mg/kg, six days/week for four weeks) was administered via oral gavage, and the rats were given swim exercise one hour/day, five days/week for four weeks. Changes in memory were evaluated using Radial Arm Water Maze (RAWM) and Oxidative stress biomarkers were examined in the hippocampus.

Results: WP exposure induced short-term/long-term memory impairment (p <0.05). This impairment was prevented by a combination of VitE with SE (p <0.05). Additionally, this combination normalized the hippocampal catalase, GPx, GSH/GSSG ratios that were modulated by WP (p <0.05). The combination further reduced TBARs levels below the control group (p <0.05).

Conclusion: WP induced memory impairments were prevented by the combination of VitE with SE. This could be attributed to preserving the hippocampal oxidative mechanism by the combination of VitE and SE during WP exposure.

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Alpha-tocotrienol enhances arborization of primary hippocampal neurons via upregulation of Bcl-xL

Han-A Park, Kristi M Crowe-White, Lukasz Ciesla, Madison Scott, Sydni Bannerman, Abigail U Davis, Bishnu Adhikari, Garrett Burnett, Katheryn Broman, Khondoker Adeba Ferdous, Kimberly H Lackey, Pawel Licznerski, Elizabeth A Jonas

Nutr Res . 2022 Mar 7;101:31-42. doi: 10.1016/j.nutres.2022.02.007. Online ahead of print.


Alpha-tocotrienol (α-TCT) is a member of the vitamin E family. It has been reported to protect the brain against various pathologies including cerebral ischemia and neurodegeneration. However, it is still unclear if α-TCT exhibits beneficial effects during brain development. We hypothesized that treatment with α-TCT improves intracellular redox homeostasis supporting normal development of neurons. We found that primary hippocampal neurons isolated from rat feti grown in α-TCT-containing media achieved greater levels of neurite complexity compared to ethanol-treated control neurons. Neurons were treated with 1 μM α-TCT for 3 weeks, and media were replaced with fresh α-TCT every week. Treatment with α-TCT increased α-TCT levels (26 pmol/mg protein) in the cells, whereas the control neurons did not contain α-TCT. α-TCT-treated neurons produced adenosine triphosphate (ATP) at a higher rate and increased ATP retention at neurites, supporting formation of neurite branches. Although treatment with α-TCT alone did not change neuronal viability, neurons grown in α-TCT were more resistant to death at maturity. We further found that messenger RNA and protein levels of B-cell lymphoma-extra large (Bcl-xL) are increased by α-TCT treatment without inducing posttranslational cleavage of Bcl-xL. Bcl-xL is known to enhance mitochondrial energy production, which improves neuronal function including neurite outgrowth and neurotransmission. Therefore α-TCT-mediated Bcl-xL upregulation may be the central mechanism of neuroprotection seen in the α-TCT-treated group. In summary, treatment with α-TCT upregulates Bcl-xL and increases ATP levels at neurites. This correlates with increased neurite branching during development and with protection of mature neurons against oxidative stress.

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The tocopherol transfer protein mediates vitamin E trafficking between cerebellar astrocytes and neurons

L Ulatowski, Mikel Ghelfi, Ryan West, J Atkinson, C J Finno, D Manor

J Biol Chem . 2022 Mar;298(3):101712. doi: 10.1016/j.jbc.2022.101712. Epub 2022 Feb 9.


Alpha-tocopherol (vitamin E) is an essential nutrient that functions as a major lipid-soluble antioxidant in humans. The alpha-tocopherol transfer protein (TTP) binds α-tocopherol with high affinity and selectivity and regulates whole-body distribution of the vitamin. Heritable mutations in the TTPA gene result in familial vitamin E deficiency, elevated indices of oxidative stress, and progressive neurodegeneration that manifest primarily in spinocerebellar ataxia. Although the essential role of vitamin E in neurological health has been recognized for over 50 years, the mechanisms by which this essential nutrient is transported in the central nervous system are poorly understood. Here we found that, in the murine cerebellum, TTP is selectively expressed in glial fibrillary acidic protein-positive astrocytes, where it facilitates efflux of vitamin E to neighboring neurons. We also show that induction of oxidative stress enhances the transcription of the TtpA gene in cultured cerebellar astrocytes. Furthermore, secretion of vitamin E from astrocytes is mediated by an ABC-type transporter, and uptake of the vitamin into neurons involves the low-density lipoprotein receptor-related protein 1. Taken together, our data indicate that TTP-expressing astrocytes control the delivery of vitamin E from astrocytes to neurons, and that this process is homeostatically responsive to oxidative stress. These are the first observations that address the detailed molecular mechanisms of vitamin E transport in the central nervous system, and these results have important implications for understanding the molecular underpinnings of oxidative stress-related neurodegenerative diseases.

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Vitamin E Decreases Cytotoxicity and Mitigates Inflammatory and Oxidative Stress Responses in a Ferret Organotypic Brain Slice Model of Neonatal Hypoxia-Ischemia

Sarah Kolnik, Kylie Corry, Kate Hildahl, Jeremy Filteau, Olivia White, Olivia Brandon, Lily Farid, AnnaMarie Shearlock, Daniel Moralejo, Sandra E Juul, Elizabeth Nance, Thomas R Wood

Dev Neurosci . 2022 Feb 8. doi: 10.1159/000522485. Online ahead of print.


The gyrencephalic ferret brain is an excellent model in which to study hypoxia-ischemia (HI), a significant contributor to neurological injury in neonates. Vitamin E, an essential fat-soluble antioxidant, reduces oxidative stress and inflammation in both animal models and neonates. The aim of this study was to assess the effects of Vitamin E after oxygen glucose deprivation (OGD) in an organotypic ferret brain slice model of neonatal HI. We hypothesized that Vitamin E would decrease cytotoxicity, inflammation, and oxidative stress in OGD-exposed brain slices. Term-equivalent ferrets were sacrificed at postnatal (P) day 21-23 and 300µM whole hemisphere brain slices were obtained. During a 24h rest period, slices were cultured in either non-treated control conditions or with Erastin, a promotor of oxidative stress. Slices were then exposed to 2h of OGD followed by Vitamin E (25-100 IU/kg), Erastin (10µM) or Ferrostatin (1µM), an inhibitor of ferroptosis. Relative cytotoxicity was determined using an LDH assay, cell death was quantified via nuclear propidium iodide (PI) staining, oxidative stress was quantified via cellular GSH (glutathione) levels and target genes responsive to oxidative stress and inflammation were evaluated by qRT-PCR. OGD increased cytotoxicity, which was significantly reduced by treatment with Vitamin E. Vitamin E also preserved GSH after OGD and decreased amplification of certain markers of oxidative stress (CHAC1, SLC7A11) and inflammation (TNF-alpha, IL-8). Vitamin E remained protective after pretreatment with Erastin and was more protective than Ferrostatin, presumably due to its added anti-inflammatory properties. Results from the ferret whole hemisphere OGD model support the premise that Vitamin E neuroprotection is mediated by restoring GSH and acutely decreasing inflammation and oxidative stress after neonatal HI brain injury.

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Vitamin E prevents lipid peroxidation and iron accumulation in PLA2G6-Associated Neurodegeneration

Irene Villalón-García, Mónica Álvarez-Córdoba, Suleva Povea-Cabello, Marta Talaverón-Rey, Marina Villanueva-Paz, Raquel Luzón-Hidalgo, Juan M Suárez-Rivero 1, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, Joaquín J Salas, Rafael Falcón-Moya, Antonio Rodríguez-Moreno, José A Armengol, José A Sánchez-Alcázar

Neurobiol Dis . 2022 Feb 2;105649. doi: 10.1016/j.nbd.2022.105649. Online ahead of print.


Background: PLA2G6-Associated Neurodegeneration (PLAN) is a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the NBIA (Neurodegeneration with Brain Iron Accumulation) group. Although the pathogenesis of the disease remains largely unclear, lipid peroxidation seems to play a central role in the pathogenesis. Currently, there is no cure for the disease.

Objective: In this work, we examined the presence of lipid peroxidation, iron accumulation and mitochondrial dysfunction in two cellular models of PLAN, patients-derived fibroblasts and induced neurons, and assessed the effects of α-tocopherol (vitamin E) in correcting the pathophysiological alterations in PLAN cell cultures.

Methods: Pathophysiological alterations were examined in fibroblasts and induced neurons generated by direct reprograming. Iron and lipofuscin accumulation were assessed using light and electron microscopy, as well as biochemical analysis techniques. Reactive Oxygen species production, lipid peroxidation and mitochondrial dysfunction were measured using specific fluorescent probes analysed by fluorescence microscopy and flow cytometry.

Results: PLAN fibroblasts and induced neurons clearly showed increased lipid peroxidation, iron accumulation and altered mitochondrial membrane potential. All these pathological features were reverted with vitamin E treatment.

Conclusions: PLAN fibroblasts and induced neurons reproduce the main pathological alterations of the disease and provide useful tools for disease modelling. The main pathological alterations were corrected by Vitamin E supplementation in both models, suggesting that blocking lipid peroxidation progression is a critical therapeutic target.

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Ultrasensitive detection of vitamin E by signal conversion combined with core-satellite structure-based plasmon coupling effect

Keying Xu, Jing Li, Qingyi Han, Dingding Zhang, Libing Zhang, Zhen Zhang, Xiaoquan Lu

Analyst . 2022 Jan 31;147(3):398-403. doi: 10.1039/d1an02289j.


The rapid and sensitive surface-enhanced Raman scattering (SERS) detection of molecular biomarkers from real samples is still a challenge because the intrinsically trace analytes may have a low molecular affinity for metal surfaces. Herein, we develop a smart signal conversion and amplification strategy based on silver-gold-silica core-satellite structure nanoparticles (Ag@Au@SiO2 NPs) to sensitively detect low adsorptive vitamin E using SERS, which has been considered a biomarker of neuromuscular disorders when its abnormal content is measured in the serum of patients. Through the reducibility of vitamin E, Ag+ ions are rapidly reduced to Ag atoms, resulting in the epitaxial growth of Ag nanocrystals on gold nanoparticles forming satellite particle-particle gap-narrowed Ag@Au@SiO2 NPs. The generated strong plasmonic field dramatically enhances the Raman signal of the Raman reporter molecule 4-aminothiophenol (4-ATP) and the detected vitamin E molecules at an estimated level of 58.19 nmol L-1. The sensitivity of this operational SERS strategy provides tremendous prospects for the screening of neuromuscular disorders.

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Tocotrienols protect differentiated SH-SY5Y human neuroblastoma cells against 6-hydroxydopamine-induced cytotoxicity by ameliorating dopamine biosynthesis and dopamine receptor D2 gene expression

Kasthuri Bai Magalingam, Sushela Devi Somanath, Shadab Md, Nagaraja Haleagrahara, Ju-Yen Fu, Kanga Rani Selvaduray, Ammu Kutty Radhakrishnan

Nutr Res . 2021 Dec 28;98:27-40. doi: 10.1016/j.nutres.2021.09.003. Online ahead of print.


Oxidative stress is a critical factor that triggers a “domino” cascade of events leading to the degeneration of dopaminergic neurons in Parkinson disease. Tocotrienols (T3) have antioxidant effects and can protect neuronal cells against oxidative damage. In the present study, we investigated the neuroprotective effects of different forms of T3 (alpha, delta, gamma) or tocotrienol-rich fraction (TRF) against 6-hydroxydopamine (6-OHDA)-induced oxidative damage in differentiated SH-SY5Y human neural cells. Differentiating the SH-SY5Y cells with retinoic acid and a low-serum culture medium for 6 days allowed development of human dopamine-like neural cells. Subsequently, the differentiated SH-SY5Y neural cells were pretreated with different forms of T3 for 24 hours before these cells were exposed to 6-OHDA. The T3 analogues and TRF displayed neuroprotective effects (P < .05) via restoration of cell viability and activation of antioxidant enzymes (e.g., superoxide dismutase, catalase). Notably, TRF was highly efficient in scavenging reactive oxygen species and upregulating dopamine and tyrosine hydroxylase levels in the differentiated SH-SY5Y cells. Gamma-T3 exhibited the most potent effects in attenuating apoptosis, whereas alpha-T3 was most effective in preventing 6-OHDA-induced leakage of α-Synuclein. Delta-T3 displayed a noticeable effect in upregulating the dopamine receptor D2 gene expression compared with controls. These findings suggest T3 isoforms and TRF demonstrate significant neuroprotective effects in protecting differentiated neural cells against 6-OHDA-mediated oxidative stress.

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