Neurobiological Correlates of Alpha-Tocopherol Antiepileptogenic Effects and MicroRNA Expression Modulation in a Rat Model of Kainate-Induced Seizures.

Ambrogini P, Albertini MC, Betti M, Galati C, Lattanzi D, Savelli D, Di Palma M, Saccomanno S, Bartolini D, Torquato P, Ruffolo G, Olivieri F, Galli F, Palma E, Minelli A, Cuppini R

Mol Neurobiol. 2018 Feb 22. doi: 10.1007/s12035-018-0946-7. [Epub ahead of print]

Abstract

Seizure-triggered maladaptive neural plasticity and neuroinflammation occur during the latent period as a key underlying event in epilepsy chronicization. Previously, we showed that α-tocopherol (α-T) reduces hippocampal neuroglial activation and neurodegeneration in the rat model of kainic acid (KA)-induced status epilepticus (SE). These findings allowed us to postulate an antiepileptogenic potential for α-T in hippocampal excitotoxicity, in line with clinical evidence showing that α-T improves seizure control in drug-resistant patients. To explore neurobiological correlates of the α-T antiepileptogenic role, rats were injected with such vitamin during the latent period starting right after KA-induced SE, and the effects on circuitry excitability, neuroinflammation, neuronal death, and microRNA (miRNA) expression were investigated in the hippocampus. Results show that in α-T-treated epileptic rats, (1) the number of population spikes elicited by pyramidal neurons, as well as the latency to the onset of epileptiform-like network activity recover to control levels; (2) neuronal death is almost prevented; (3) down-regulation of claudin, a blood-brain barrier protein, is fully reversed; (4) neuroinflammation processes are quenched (as indicated by the decrease of TNF-α, IL-1β, GFAP, IBA-1, and increase of IL-6); (5) miR-146a, miR-124, and miR-126 expression is coherently modulated in hippocampus and serum by α-T. These findings support the potential of a timely intervention with α-T in clinical management of SE to reduce epileptogenesis, thus preventing chronic epilepsy development. In addition, we suggest that the analysis of miRNA levels in serum could provide clinicians with a tool to evaluate disease evolution and the efficacy of α-T therapy in SE.

Soares-Weiser K, Maayan N, Bergman H

Cochrane Database Syst Rev. 2018 Jan 17;1:CD000209. doi: 10.1002/14651858.CD000209.pub3. [Epub ahead of print]

Abstract

BACKGROUND:

Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) – a problem often seen as repetitive involuntary movements around the mouth and face. Vitamin E has been proposed as a treatment to prevent or decrease TD.

OBJECTIVES:

The primary objective was to determine the clinical effects of vitamin E in people with schizophrenia or other chronic mental illness who had developed antipsychotic-induced TD.The secondary objectives were:1. to examine whether the effect of vitamin E was maintained as duration of follow-up increased;2. to test the hypothesis that the use of vitamin E is most effective for those with early onset TD (less than five years) SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information.

SELECTION CRITERIA:

We included reports if they were controlled trials dealing with people with antipsychotic-induced TD and schizophrenia who remained on their antipsychotic medication and had been randomly allocated to either vitamin E or to a placebo, no intervention, or any other intervention.

DATA COLLECTION AND ANALYSIS:

We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who left early had no improvement. We assessed risk of bias and created a ‘Summary of findings’ table using GRADE.

MAIN RESULTS:

The review now includes 13 poorly reported randomised trials (total 478 people), all participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. There was no clear difference between vitamin E and placebo for the outcome of TD: not improved to a clinically important extent (6 RCTs, N = 264, RR 0.95, 95% CI 0.89 to 1.01, low-quality evidence). However, people allocated to placebo may show more deterioration of their symptoms compared with those given vitamin E (5 RCTs, N = 85, RR 0.23, 95% CI 0.07 to 0.76, low-quality evidence). There was no evidence of a difference in the incidence of any adverse effects (9 RCTs, N = 205, RR 1.21, 95% CI 0.35 to 4.15, very low-quality evidence), extrapyramidal adverse effects (1 RCT, N = 104, MD 1.10, 95% CI -1.02 to 3.22, very low-quality evidence), or acceptability of treatment (measured by participants leaving the study early) (medium term, 8 RCTs, N = 232, RR 1.07, 95% CI 0.64 to 1.80, very low-quality evidence). No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, outcomes designated important to patients. There is no trial-based information regarding the effect of vitamin E for those with early onset of TD.

AUTHORS’ CONCLUSIONS:

Small trials of limited quality suggest that vitamin E may protect against deterioration of TD. There is no evidence that vitamin E improves symptoms of this problematic and disfiguring condition once established. New and better trials are indicated in this under-researched area, and, of the many adjunctive treatments that have been given for TD, vitamin E would be a good choice for further evaluation.

Apostolopoulou K, Konstantinou D, Alataki R, Papapostolou I, Zisimopoulos D, Kalaitzopoulou E, Bravou V, Lilis I, Angelatou F, Papadaki H, Georgiou CD, Chroni E

Neurochem Res. 2018 Jan 11. doi: 10.1007/s11064-017-2465-8. [Epub ahead of print]

Abstract

An ischemia/reperfusion injury of rat’s sciatic nerve was experimentally developed. In this model, we measured the in vivo production of superoxide radical, as a marker of oxidative stress and the occludin expression as an indicator of blood-nerve barrier function and we examined potential protective innervations against these abnormalities. Right sciatic nerves of the animals underwent 3 h of ischemia followed by 7 days of reperfusion and were divided into three groups: ischemic, pretreated with vitamin C in conjunction with vitamin E and treated with tissue plasminogen activator. Compared to measurements from left sciatic nerves used as sham, the ischemic group showed significantly increased superoxide radical and reduced expression of occludin in western blot and immunohistochemistry. No such differences were detected between sham and nerves in the vitamin or tissue plasminogen activator groups. It is suggested that the experimental ischemia/reperfusion model was suitable for studying the relationship between oxidative state and blood-nerve barrier. The reversion of abnormalities by the applied neuroprotective agents might prove to be a clinically important finding in view of the implication of vascular supply derangement in various neuropathies in humans.

Marcos P, González-Fuentes J, Castro-Vázquez L, Lozano MV, Santander-Ortega MJ, Rodríguez-Robledo V, Villaseca-González N, Arroyo-Jiménez MM

J Anat. 2018 Jan 8. doi: 10.1111/joa.12769. [Epub ahead of print]

Abstract

Its high metabolic rate and high polyunsaturated fatty acid content make the brain very sensitive to oxidative damage. In the brain, neuronal metabolism occurs at a very high rate and generates considerable amounts of reactive oxygen species and free radicals, which accumulate inside neurons, leading to altered cellular homeostasis and integrity and eventually irreversible damage and cell death. A misbalance in redox metabolism and the subsequent neurodegeneration increase throughout the course of normal aging, leading to several age-related changes in learning and memory as well as motor functions. The neuroprotective function of antioxidants is crucial to maintain good brain homeostasis and adequate neuronal functions. Vitamins E and C are two important antioxidants that are taken up by brain cells via the specific carriers αTTP and SVCT2, respectively. The aim of this study was to use immunohistochemistry to determine the distribution pattern of these vitamin transporters in the brain in a mouse model that shows fewer signs of brain aging and a higher resistance to oxidative damage. Both carriers were distributed widely throughout the entire brain in a pattern that remained similar in 4-, 12-, 18- and 24-month-old mice. In general, αTTP and SVCT2 were located in the same regions, but they seemed to have complementary distribution patterns. Double-labeled cell bodies were detected only in the inferior colliculus, entorhinal cortex, dorsal subiculum, and several cortical areas. In addition, the presence of αTTP and SVCT2 in neurons was analyzed using double immunohistochemistry for NeuN and the results showed that αTTP but not SVCT2 was present in Bergmann’s glia. The presence of these transporters in brain regions implicated in learning, memory and motor control provides an anatomical basis that may explain the higher resistance of this animal model to brain oxidative stress, which is associated with better motor performance and learning abilities in old age.

Rafati A, Noorafshan A, Jahangir M, Hosseini L, Karbalay-Doust S

Acta Histochem. 2018 Jan;120(1):46-55. doi: 10.1016/j.acthis.2017.11.004. Epub 2017 Nov 21.

Abstract

Aspartame is an artificial sweetener used in about 6000 sugar-free products. Aspartame consumption could be associated with various neurological disorders. This study aimed to evaluate the effect of aspartame onmedial Prefrontal Cortex (mPFC) as well as neuroprotective effects of vitamin E. The rats were divided into seven groups, including distilled water, corn oil, vitamin E (100mg/kg/day), and low (acceptable daily dose) and high doses of aspartame (40 and 200mg/kg/day) respectively, with or without vitamin E consumption, for 8 weeks. Behavioral tests were recorded and the brain was prepared for stereological assessments. Novel objects test and eight-arm radial maze showed impairmentoflong- and short-termmemoriesin aspartame groups. Besides, mPFC volume, infralimbic volume, neurons number, glial cells number, dendrites length per neuron,and number of spines per dendrite length were decreased by 7-61% in the rats treated with aspartame. However, neurons’ number, glial cells number, and rats’ performance in eight-arm radial mazes were improved by concomitant consumption of vitamin E and aspartame. Yet, the mPFC volume and infralimbic cortex were protected only in the rats receiving the low dose of aspartame+vitamin E. On the other hand, dendrites length, spines number,and novel object recognition were not protected by treatment with vitamin E+aspartame. The acceptable daily dose or higher doses of aspartame could induce memory impairments and cortical cells loss in mPFC. However, vitamin E could ameliorate some of these changes.

Beytut E, Yilmaz S, Aksakal M, Polat S

J Trace Elem Med Biol. 2018 Jan;45:131-135. doi: 10.1016/j.jtemb.2017.10.005. Epub 2017 Oct 16.

Abstract

Acute exposure to high doses of glucocorticoids (GCs) may potentially increase the basal levels of reactive oxygen species (ROS) by altering the defence capacity against oxidative damage. Also, antioxidants may affect the oxidative breakdown of tissues. Therefore, the aim of this work was to determine the effects of dietary intake vitamin E and selenium (Se) on lipid peroxidation (LPO) as thiobarbituric acid reactive substances (TBARS) and on the antioxidative defence mechanisms in the brain of rats treated with high doses of prednisolone. Two hundred and fifty adult male Wistar rats were randomly divided into five groups. The rats were fed a normal diet, but groups 3, 4, and 5 received a daily supplement in their drinking water of 20mg vitamin E, 0.3mg Se, and a combination of vitamin E and Se, respectively, for 30days. For 3days subsequently, the control (group 1) was treated with a placebo, and the remaining 4 groups were injected intramuscularly with 100mg/kg body weight (bw) prednisolone. After the last administration of prednisolone, 10 rats from each group were killed at 4, 8, 12, 24, and 48h and the activities of enzymes selenium-glutathione peroxidase (Se-GSH-Px) and catalase (CAT), and the levels of reduced glutathione (reduced GSH) and TBARS in their brains were measured. Se-GSH-Px and CAT enzyme activities, and reduced GSH levels in the prednisolone treatment group (group 2) began to decrease gradually at 4h (p<0.01, p<0.05, respectively), falling respectively to 60, 50, and 40% of the control levels by 24h (p<0.001, p<0.01), and recovering to the control levels at 48h. In contrast, prednisolone administration caused an increase in the brain TBARS, reaching up to six times the level of the control at 24h (p<0.001). However, supplementation with vitamin E and Se had a preventive effect on the elevation of the brain TBARS and improved the diminished activities of antioxidative enzymes and the levels of reduced GSH. Therefore, the present study attempts to determine the sequence of cellular membrane damage in the brain of the rats after high doses GC administration and the possible roles in vivo of vitamin E and Se, and their combination.

Baghcheghi Y, Beheshti F, Shafei MN, Salmani H, Sadeghnia HR, Soukhtanloo M, Anaeigoudari A, Hosseini M

Metab Brain Dis. 2017 Dec 30. doi: 10.1007/s11011-017-0176-0. [Epub ahead of print]

Abstract

The effects of vitamin E (Vit E) on brain derived neurotrophic factor (BDNF) and brain tissues oxidative damage as well as on learning and memory impairments in juvenile hypothyroid rats were examined. The rats were grouped as: (1) Control; (2) Propylthiouracil (PTU); (3) PTU-Vit E and (4) Vit E. PTU was added to their drinking water (0.05%) during 6 weeks. Vit E (20 mg/kg) was daily injected (IP). Morris water maze (MWM) and passive avoidance (PA) were carried out. The animals were deeply anesthetized and the brain tissues were removed for biochemical measurements. PTU increased the escape latency and traveled path in MWM (P < 0.001). It also shortened the latency to enter the dark compartment of PA as well as the time spent in the target quadrant in probe trial of MWM (P < 0.01-P < 0.001). All the effects of PTU were reversed by Vit E (P < 0.01-P < 0.001). PTU administration attenuated thiol and BDNF content as well as the activities of superoxide dismutase (SOD) and catalase (CAT) in the brain tissues while increased molondialdehyde (MDA). Moreover, Vit E improved BDNF, thiol, SOD and CAT while diminished MDA. The results of the present study showed that Vit E improved BDNF and prevented from brain tissues oxidative damage as well as learning and memory impairments in juvenile hypothyroid rats.

Sun B, Zhang X, Yin Y, Sun H, Ge H, Li W

J Trace Elem Med Biol. 2017 Dec;44:88-92. doi: 10.1016/j.jtemb.2017.06.004.

Abstract

OBJECT:

To investigate the effects of sulforaphane (SFN) and vitamin E (VE) on spatial learning and memory ability and oxidative damage of hippocampus in lead-exposed mice at lactation.

METHODS:

A total of 18 adult Kunming mice, all 12 female mice were divided into two groups by body weight randomly, 10 mice drank water containing 0.2% lead acetate at lactation, the other 2 mice drank lead free deionized water named as the normal group. Then, they were mated at a 1:2 ratio of male to female. After weaning, the pups were divided into 5 groups by weight randomly (10 each group): normal saline (NS) group, corn oil (CO) group, SFN group, VE group and SFN+VE group. They were subject to gavage daily for four weeks. Gavage doses of SFN and VE were 25mg/kg and 30 IU/kg respectively. Meanwhile, 10 pups of the normal group were selected randomly as the control (C) group. The C group was normally raised for 4 weeks. The spatial learning and memory ability of them were evaluated by the Morris water maze test, and the lead level in the blood was determined by polarography. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) level in hippocampus were measured by the kits.

RESULTS:

Compared with the NS and CO groups, the lead level in the blood of SFN and SFN+VE group had a significant decrease. In water maze test, the mice treated with SFN or/and VE performed better than mice of the NS and CO groups. In addition, a remarkable decrease in MDA level was found in mice treated with SFN or/and VE than those in NS and CO groups. What’s more, there was no statistical distinction of SOD activity in SFN group than that of NS group. SOD activity significantly increased was observed in VE and SFN+VE groups than that of CO group.

CONCLUSION:

Sulforaphane and vitamin E could ameliorate cognitive decline and oxidative damage in pups with lead exposure at lactation from maternal milk.

Kanchi MM, Shanmugam MK, Rane G, Sethi G, Kumar AP

Drug Discov Today. 2017 Dec;22(12):1765-1781. doi: 10.1016/j.drudis.2017.08.001. Epub 2017 Aug 5.

Abstract

Vitamin E family members: tocotrienols and tocopherols are widely known for their health benefits. Decades of research on tocotrienols have shown they have diverse biological activities such as antioxidant, anti-inflammatory, anticancer, neuroprotective and skin protection benefits, as well as improved cognition, bone health, longevity and reduction of cholesterol levels in plasma. Tocotrienols also modulate several intracellular molecular targets and, most importantly, have been shown to improve lipid profiles, reduce total cholesterol and reduce the volume of white matter lesions in human clinical trials. This review provides a comprehensive update on the little-known therapeutic potentials of tocotrienols, which tocopherols lack in a variety of inflammation-driven diseases.

Abedi Z, Khaza'ai H, Vidyadaran S, Mutalib MSA

Biomedicines. 2017 Dec 1;5(4). pii: E68. doi: 10.3390/biomedicines5040068.

Abstract

Astrocytes are known as structural and supporting cells in the central nervous system (CNS). Glutamate, as a main excitatory amino acid neurotransmitter in the mammalian central nervous system, can be excitotoxic, playing a key role in many chronic neurodegenerative diseases. The aim of the current study was to elucidate the potential of vitamin E in protecting glutamate-injured primary astrocytes. Hence, primary astrocytes were isolated from mixed glial cells of C57BL/6 mice by applying the EasySep^® Mouse CD11b Positive Selection Kit, cultured in Dulbecco’s modified Eagle medium (DMEM) and supplemented with special nutrients. The IC₂₀ and IC₅₀ values of glutamate, as well as the cell viability of primary astrocytes, were assessed with 100 ng/mL, 200 ng/mL, and 300 ng/mL of tocotrienol-rich fraction (TRF) and alpha-tocopherol (α-TCP), as determined by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The mitochondrial membrane potential (MMP) detected in primary astrocytes was assessed with the same concentrations of TRF and α-TCP. The expression levels of the ionotropic glutamate receptor genes (Gria2, Grin2A, GRIK1) were independently determined using RT-PCR. The purification rate of astrocytes was measured by a flow-cytometer as circa 79.4%. The IC₂₀ and IC₅₀ values of glutamate were determined as 10 mM and 100 mM, respectively. Exposure to 100 mM of glutamate in primary astrocytes caused the inhibition of cell viability of approximately 64.75% and 61.10% in pre- and post-study, respectively (p < 0.05). Both TRF and α-TCP (at the lowest and highest concentrations, respectively) were able to increase the MMP to 88.46% and 93.31% pre-treatment, and 78.43% and 81.22% post-treatment, respectively. Additionally, the findings showed a similar pattern for the expression level of the ionotropic glutamate receptor genes. Increased extracellular calcium concentrations were also observed, indicating that the presence of vitamin E altered the polarization of astrocytes. In conclusion, α-TCP showed better recovery and prophylactic effects as compared to TRF in the pre-treatment of glutamate-injured primary astrocytes.