Transcriptomic Analysis of MAPK Signaling in NSC-34 Motor Neurons Treated with Vitamin E

Chiricosta L, Gugliandolo A, Tardiolo G, Bramanti P, Mazzon E

Nutrients. 2019 May 15;11(5). pii: E1081. doi: 10.3390/nu11051081.

Abstract

Vitamin E family is composed of different tocopherols and tocotrienols that are well-known as antioxidants but that exert also non-antioxidant effects. Oxidative stress may be involved in the progression of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), characterized by motor neuron death. The aim of the study was the evaluation of the changes induced in the transcriptional profile of NSC-34 motor neurons treated with α-tocopherol. In particular, cells were treated for 24 h with 10 µM α-tocopherol, RNA was extracted and transcriptomic analysis was performed using Next Generation Sequencing. Vitamin E treatment modulated MAPK signaling pathway. The evaluation revealed that 34 and 12 genes, respectively belonging to “Classical MAP kinase pathway” and “JNK and p38 MAP kinase pathway”, were involved. In particular, a downregulation of the genes encoding for p38 (Log₂ fold change -0.87 and -0.67) and JNK (Log₂ fold change -0.16) was found. On the contrary, the gene encoding for ERK showed a higher expression in cells treated with vitamin E (Log₂ fold change 0.30). Since p38 and JNK seem more involved in cell death, while ERK in cell survival, the data suggested that vitamin E treatment may exert a protective role in NSC-34 motor neurons. Moreover, Vitamin E treatment reduced the expression of the genes which encode proteins involved in mitophagy. These results indicate that vitamin E may be an efficacious therapy in preventing motor neuron death, opening new strategies for those diseases that involve motor neurons, including ALS.

Liu X, Zhang Y, Yang X

Ecotoxicol Environ Saf. 2019 May 15;172:33-39. doi: 10.1016/j.ecoenv.2019.01.048. Epub 2019 Jan 19.

Abstract

Exposure to specific air pollutants has been demonstrated to induce damage in the brain. However, these studies ignore the effects of a combination of contaminants, and there is a high likelihood that people will be exposed to a mixture of contaminants in daily life. Our previous study showed that co-exposure to formaldehyde (FA) and PM2.5 induced damage in the mouse brain at the safe exposure level for FA or PM2.5 exposure alone, and that oxidative stress and inflammation may be involved in the toxicity mechanisms. A universal strategy to protect people exposed to FA and PM2.5 is urgently needed. To explore whether an exogenous substance could counteract the negative effects of exposure to these pollutants, we administered vitamin E (Vit E) to the experimental animals. The results showed that administration of Vit E in tandem with the FA and PM2.5 co-exposure, reduced the extent of damage to the mouse brain. Down-regulation of oxidative stress and inflammation were proposed to explain the protective effects of Vit E. This research provides a universal strategy to effectively protect people who are exposed to FA and PM2.5 simultaneously.

Nesari A, Mansouri MT, Khodayar MJ, Rezaei M

Nutr Neurosci. 2019 May 14:1-11. doi: 10.1080/1028415X.2019.1601888. [Epub ahead of print]

Abstract

OBJECTIVE:

The ubiquitin-proteasome system plays a key role in memory consolidation. Proteasome inhibition and free radical-induced neural damage were implicated in neurodegenerative states. In this study, it was tested whether alpha-tocopherol (αT) in low and high doses could improve the long-term memory impairment induced by proteasome inhibition and protects against hippocampal oxidative stress.

METHODS:

Alpha-tocopherol (αT) (60, 200 mg/kg, i.p. for 5 days) was administered to rats with memory deficit and hippocampal oxidative stress induced by bilateral intra-hippocampal injection of lactacystin (32 ng/μl) and mitochondrial evaluations were performed for improvement assessments.

RESULTS:

The results showed that lactacystin significantly reduced the passive avoidance memory performance and increased the level of malondialdehyde (MDA), reactive oxygen species (ROS) and diminished the mitochondrial membrane potential (MMP) in the rat hippocampus. Furthermore, Intraperitoneal administration of αT significantly increased the passive avoidance memory, glutathione content and reduced ROS, MDA levels and impaired MMP.

CONCLUSIONS:

The results suggested that αT has neuroprotective effects against lactacystin-induced oxidative stress and memory impairment via the enhancement of hippocampal antioxidant capacity and concomitant mitochondrial sustainability. This finding shows a way to prevent and also to treat neurodegenerative diseases associated with mitochondrial impairment.

Elfakhri KH, Abdallah IM, Brannen AD, Kaddoumi A

Neurobiol Dis. 2019 May;125:123-134. doi: 10.1016/j.nbd.2019.01.020. Epub 2019 Jan 30.

Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with multiple dysfunctional pathways. Therefore, a sophisticated treatment strategy that simultaneously targets multiple brain cell types and disease pathways could be advantageous for effective intervention. To elucidate an effective treatment, we developed an in vitro high-throughput screening (HTS) assay to evaluate candidate drugs for their ability to enhance the integrity of the blood-brain barrier (BBB) and improve clearance of amyloid-β (Aβ) using a cell-based BBB model. Results from HTS identified etodolac and α-tocopherol as promising drugs for further investigation. Both drugs were tested separately and in combination for the purpose of targeting multiple pathways including neuroinflammation and oxidative stress. In vitro studies assessed the effects of etodolac and α-tocopherol individually and collectively for BBB integrity and Aβ transport, synaptic markers and Aβ production in APP-transfected neuronal cells, as well as effects on inflammation and oxidative stress in astrocytes. Transgenic 5XFAD mice were used to translate in vitro results of etodolac and α-tocopherol independently and with concurrent administration. Compared to either drug alone, the combination significantly enhanced the BBB function, decreased total Aβ load correlated with increased expression of major transport proteins, promoted APP processing towards the neuroprotective and non-amyloidogenic pathway, induced synaptic markers expression, and significantly reduced neuroinflammation and oxidative stress both in vitro and in vivo. Collective findings demonstrated the combination produced mixed interaction showing additive, less than additive or synergistic effects on the evaluated markers. In conclusion, this study highlights the significance of combination therapy to simultaneously target multiple disease pathways, and suggest the repurposing and combination of etodolac and α-tocopherol as a novel therapeutic strategy against AD.

Casati M, Boccardi V, Ferri E, Bertagnoli L, Bastiani P, Ciccone S, Mansi M, Scamosci M, Rossi PD, Mecocci P, Arosio B

Aging Clin Exp Res. 2019 May 3. doi: 10.1007/s40520-019-01209-3. [Epub ahead of print]

Abstract

BACKGROUND:

Vitamin E represents a potent antioxidant and anti-inflammatory system, playing a role in Alzheimer’s disease (AD). Different plasma concentrations of the forms of vitamin E are observed in AD compared to cognitively healthy subjects.

AIM:

Since these modifications may modulate the markers of oxidative stress and cellular aging, we aim to explore the relationship between vitamin E forms and leukocyte telomere length (LTL) in AD.

METHODS:

53 AD subjects and 40 cognitively healthy controls (CTs) were enrolled. The vitamin E forms (α-, β-, γ- and δ-tocopherol, α-, β-, γ- and δ-tocotrienol), the ratio of α-tocopherylquinone/α-tocopherol and 5-nitro-γ-tocopherol/γ-tocopherol (markers of oxidative/nitrosative damage) and LTL were measured.

RESULTS AND DISCUSSION:

Regression model was used to explore the associations of vitamin E forms and LTL with AD. The interaction of LTL in the association between vitamin E forms and AD was tested. AD subjects showed significantly lower concentrations of α-, β-, γ- and δ-tocopherol, α- and δ-tocotrienol, total tocopherols, total tocotrienols and total vitamin E compared to CTs. AD subjects showed higher values of nitrosative/oxidative damage. The adjusted analyses confirmed a significant relationship of AD with plasma concentrations of α- and β-tocopherols, δ-tocotrienol, total tocopherols, total tocotrienol, total vitamin E and oxidative/nitrosative damage. However, nitrosative damage was significantly associated with AD only in subjects with higher LTL and not in those expressing marked cellular aging.

CONCLUSIONS:

Our study confirms the role of vitamin E in AD pathology and indicates that nitrosative damage influences the association with AD only in subjects characterized by longer LTL.

Alzoubi KH, Hasan ZA, Khabour OF, Mayyas FA, Al Yacoub ON, Banihani SA, Alomari MA, Alrabadi NN

Physiol Behav. 2019 Apr 13;206:200-205. doi: 10.1016/j.physbeh.2019.04.011. [Epub ahead of print]

Abstract

There is increasing evidence that oxidative stress is a causal factor in different neurodegenerative disorders such as Alzheimer’s disease and epilepsy. High-fat diet (HFD) has been shown to induce oxidative stress and neuronal damage that may increase susceptibility to seizures. The present study was undertaken to investigate the relationships between vitamin E, a potent antioxidant, HFD, and chemically induced seizures, using the PTZ seizure model in rats. Animals were randomly assigned into four groups: control, HFD, vitamin E (Vit E), and high-fat diet with vitamin E (HFD + Vit E) group. Vitamin E and/or HFD were administered to animals for 6 weeks. Thereafter, PTZ seizure threshold was measured in control and treated rats, and different brain regions were analyzed for levels of oxidative stress biomarkers. Current results revealed a significant reduction in PTZ seizure threshold in rats consuming HFD, which could be prevented by vitamin E supplement. Alongside, vitamin E supplement prevented HFD induced changes in oxidative stress biomarkers and capacity enzymes. Therefore, current results suggest that prolonged consumption of HFD increases susceptibility to PTZ induced seizures, which may be related to HFD induced oxidative stress. This increase in the PTZ susceptibility could be prevented by the administration of vitamin E, probably through its antioxidant effect, particularly at the brain hippocampal region.

Wang W, Li J, Zhang H, Wang X, Zhang X

Nutr Neurosci. 2019 Mar 22:1-10. doi: 10.1080/1028415X.2019.1585506. [Epub ahead of print]

Abstract

OBJECTIVE:

The association between vitamin E supplementation and Alzheimer’s disease (AD) was controversial because of conflicting data in the literature. This study was designed to systematically evaluate evidence about the efficacy of vitamin E supplementation not only on the risk but also on the progression of AD.

DESIGN:

Five electronic databases were searched for studies published up to June 2017. Articles reporting vitamin E supplementation and AD were included, and the random-effect model was performed for the meta-analysis about the relationship between vitamin Esupplementation and AD.

RESULTS:

Five cohort studies and three randomized controlled trial (RCT) studies (total n = 14,262) involving 1313 cases about vitamin Eeffects on the risk of AD and 244 cases about effects on progression of AD. The pooled RR for vitamin E supplemental and risk of AD was 0.81 [95% CI: 0.50-1.33, I² = 69.2%]. Suitable data could not be extracted to do meta-analysis as there was no unified standard of outcome measure for studies on AD progression. We carefully analyzed and evaluated the authenticity and accuracy of every single trial, while reliable evidence could not be obtained.

CONCLUSIONS:

From what we do, neither the synthetic data on risk of AD nor the critical review on progression of AD could provide enough evidence on our research. Thus, we cannot draw a specific conclusion on the association or correlation between Vitamin E and AD.

Takahashi K, Yanai S, Takisawa S, Kono N, Arai H, Nishida Y, Yokota T, Endo S, Ishigami A

Arch Biochem Biophys. 2019 Mar 15;663:120-128. doi: 10.1016/j.abb.2019.01.003. Epub 2019 Jan 8.

Abstract

BACKGROUND:

Vitamin C (l-ascorbic acid, VC) and vitamin E (α-tocopherol, VE) play important physiological roles as endogenous antioxidants in many tissues and organs. However, their roles in the brain remain entirely elusive. We established senescence marker protein 30 (SMP30)/α-tocopherol transfer protein (αTTP) double knockout (DKO) mice as a novel VC and VE double-deficiency model and examined the effect of VC and VE double-deficiency on brain functions.

METHODS:

DKO and wild-type (WT) mice were divided into the following two groups: mice in the CE (+) group were supplied with sufficient amounts of VC and VE and mice in the CE (-) group were deficient in both VC and VE. After 8 weeks of CE (+) or CE (-) treatments, a battery of behavioral experiments was conducted to analyze cognitive functions, including memory, through the Morris water maze and Pavlovian fear conditioning tasks.

RESULTS:

The plasma VC and VE levels in DKO-CE (-) mice and VE level in WT-CE (-) mice were almost completely depleted after 8 weeks of the deficient treatment. The behavioral study revealed that the general behaviors, including locomotor activity and anxiety level, were not influenced by the CE (-) treatment in DKO and WT mice. However, in the Pavlovian fear conditioning task, DKO-CE (-) mice showed impaired conditioned fear memory compared with that of DKO-CE (+) mice. Furthermore, increased mRNA expression was observed in inflammatory-related genes, such as IL-6, TNFα, F4/80, and Mcp-1, in the hippocampus of DKO-CE (-) mice.

CONCLUSIONS:

The findings of this study provide evidence that VC and VE deficiency led to impaired conditioned fear memory possibly caused by neuroinflammation in the brain.

Ekicier Acar S, Sarıcaoğlu MS, Çolak A, Aktaş Z, Sepici Dinçel A

Eur J Ophthalmol. 2019 Mar 11:1120672119833271. doi: 10.1177/1120672119833271. [Epub ahead of print]

Abstract

PURPOSE::

We aimed to create mechanic optic nerve injury model in rats and investigate the neuroprotective effects of topical Coenzyme Q10 + Vitamin E (CoQ + Vit.E) molecules on retinal ganglion cells.

METHODS::

Mechanic optic nerve injury model was created in the right eyes of rats (n = 12). Rats were divided into two groups: glaucoma model with sham treatment and topical CoQ + Vit.E treatment. Treatment was applied for 4 weeks. Glial fibrillary acidic protein, Brn-3a antibody, and anti-Iba1 were examined by immunohistochemistry. Glial fibrillary acidic protein, Bax, Bcl-xL, and Tfam protein expression were measured by Western blot analysis.

RESULTS::

The number of Brn-3a-positive retinal ganglion cell was 15.0 ± 1.0 (min: 14, max: 16) in sham treatment group and 22.2 ± 4.8 (min: 18, max: 29) in topical CoQ10 + Vit.E treatment group. The protection of Brn-3a in CoQ10 + Vit.E was statistically significant (p < 0.05). Glial fibrillary acidic protein-positive astroglial counts were recorded as 11.7 ± 2.1 (min: 10, max: 14) in sham treatment and 2.5 ± 1.5 (min: 1, max: 4) in topical CoQ10 + Vit.E treatment group (p < 0.05). Topical CoQ10 + Vit.E treatment also decreased Iba1 expression in the retina of mechanic optic nerve injury groups. CoQ10 + Vit.E treatment prevented apoptotic cell death by increasing Bcl-xL protein expression. Also, CoQ10 + Vit.E preserved Tfam protein expression in the retina.

CONCLUSION::

This study has shown that in glaucoma treatment the neuron protecting effect of topical CoQ10 + Vit.E molecules can be valuable.

Alzoubi KH, Halboup AM, Alomari MM, Khabour OF

Life Sci. 2019 Feb 25. pii: S0024-3205(19)30140-7. doi: 10.1016/j.lfs.2019.02.050. [Epub ahead of print]

Abstract

AIMS:

Tobacco smoking is associated with a vast range of adverse health effects, including diminished cognitive and anti-oxidative capabilities. Conversely, vitamin E (VitE) is known to enhance data acquisition and retention and hippocampal oxidative defense. No studies, however, examined the protective effect of VitE with tobacco administration. Therefore, this study examined the protective effect of VitE on the cognitive and oxidative debilitating effects induced by waterpipe smoking.

MATERIALS AND METHODS:

Wistar male rats were divided into four groups: waterpipe smoking, VitE, waterpipe combined with VitE, and control group. The exposure to waterpipe and VitE was for one month and then spatial learning and memory were assesses using Radial Arms Water Maze. Additionally, oxidative stress biomarkers (Catalase, GPx, and TBARS, GSH, GSSG, and GSH/GSSG ratio) were assessed in the hippocampus.

KEY FINDINGS:

The results revealed that waterpipe smoking impaired short-term and long-term memory (P < 0.05). Waterpipe smoking reduced activity of catalase (P < 0.05), GPx (P < 0.05) and GSH/GSSG ratio (P < 0.05) in the hippocampus. Administration of VitE prevented memory impairment and alterations in oxidative stress biomarkers.

SIGNIFICANCE:

waterpipe smoking induces short-term and long-term memory impairments, which were prevented by administration of VitE via its anti-oxidative properties.