The use of vitamin E in preventing taxane-induced peripheral neuropathy

Muhammad Ali Heiba, Soheir Sayed Ismail, Mohamed Sabry, Walid Abd Elmoniem Bayoumy, Khaled Abdel-Aziz Kamal

Cancer Chemother Pharmacol . 2021 Dec;88(6):931-939. doi: 10.1007/s00280-021-04347-6. Epub 2021 Sep 1.

Abstract

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of chemotherapy. Several trials have evaluated the protective effect of vitamin E in preventing CIPN with controversial results. This study aims to outline the role of vitamin E in preventing CIPN.

Methods: A prospective phase II, open-label randomized controlled study was conducted in patients receiving taxane-based chemotherapy in Ain Shams University Hospitals, using vitamin E at a dose of 400 mg twice daily. The primary endpoint was the incidence of grade ≥ 2 sensory neuropathy according to CTCAE v 5.0 in each treatment arm. Secondary endpoints include time to onset and the duration of grade ≥ 2 sensory neuropathy.

Results: A total of 140 patients were randomized between the control and vitamin E arms. There was no difference in the incidence of grade ≥ 2 sensory neuropathy between the two arms (25.7% in each arm; P = 1.0), as well as the time to onset of neuropathy (P = 0.24). However, there was a statistically significant difference between the 2 arms as regards the duration of neuropathy. The median duration was 12.5 vs. 5 weeks in the control and vitamin E arms respectively (P = 0.01).

Conclusion: Our study did not demonstrate a protective role of vitamin E in decreasing the incidence of CIPN in patients receiving taxane-based chemotherapy. However, the recovery from CIPN was much better as compared to the control arm, which may indicate a role for vitamin E in decreasing the duration and severity of CIPN.

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Tocotrienols reach the brain and play roles in the attenuation of body weight gain and improvement of cognitive function in high-fat diet-treated mice

Yugo Kato, Hayami Uchiumi, Ryo Usami, Hirokatsu Takatsu, Yoshinori Aoki, Shuichi Yanai, Shogo Endo, Koji Fukui

J Clin Biochem Nutr . 2021 Nov;69(3):256-264. doi: 10.3164/jcbn.21-10. Epub 2021 Jun 11.

Abstract

Obesity induces severe disorders such as type 2 diabetes and cardiovascular events, and the number of people with obesity is increasing all over the world. Furthermore, it is possible that obesity increases the risk of cognitive dysfunction via the acceleration of oxidative damage. Tocotrienols, which are part of the vitamin E family, have antioxidant and anti-obesity effects. However, the effects of tocotrienols on high-fat diet-treated mice have not been completely elucidated. In this study, we assessed changes in body weight, spatial reference memory acquisition, liver lipid droplet size, blood brain barrier-related protein expressions and antioxidative defense systems in high-fat diet-treated mice in the presence or absence of tocotrienols. The results showed that tocotrienols significantly inhibited body weight gain and lipid droplet synthesis. Although the amount was very small, it was confirmed that tocotrienols surely reached the brain in the perfused brain. Treatment with tocotrienols was tended to improve cognitive function in the control mice. However, tocotrienols did not modulate blood brain barrier-related protein expressions or antioxidative defense systems. These results indicate that treatment with tocotrienols could be effective for the prevention of obesity and cognitive dysfunction. Further extended research is needed to elucidate the relationship between anti-obesity and antioxidant effects of tocotrienols, especially in the brain.

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Modulatory Effects of Alpha- and Gamma-Tocopherol on the Mitochondrial Respiratory Capacity and Membrane Potential in an In Vitro Model of Alzheimer’s Disease

Aslina Pahrudin Arrozi, Wan Zurinah Wan Ngah, Hanafi Ahmad Damanhuri, Suzana Makpol

Front Pharmacol . 2021 Nov 22;12:698833. doi: 10.3389/fphar.2021.698833. eCollection 2021.

Abstract

Increased amyloid-beta (Aβ) and amyloid precursor protein (APP) in the brains of Alzheimer’s disease (AD) patients are common pathological hallmarks mediating the disease progression. Growing evidence also suggests that mitochondrial abnormalities are an early feature in the pathogenesis of AD. Intervention with antioxidants has received great interest as a molecular strategy for the manipulation of mitochondrial function. Our previous preliminary study using in vitro cell models expressing different types of APP demonstrated that treatment with alpha-tocopherol (ATF) or gamma-tocopherol (GTF) modulates mitochondrial function by reducing mitochondrial reactive oxygen species (ROS), increasing the production of ATP and preventing apoptosis events, especially in cells expressing the mutant APP form. Thus, we hypothesized that ATF or GTF treatment might also alter mitochondrial metabolic pathways such as oxidative phosphorylation. The present study aimed to investigate the role of ATF and GTF in modulating mitochondrial oxidative metabolism using high-resolution respirometry. Our results showed that both ATF and GTF increased the respiratory capacity and membrane potential in the ROUTINE and OXPHOSCI-LINKED states as well as complex IV enzyme activity in wild-type and mutant APP-overexpressing SH-SY5Y cells. Although preliminary, these findings indicate that ATF and GTF modulate mitochondrial oxidative metabolism in APP-overexpressing cells and, in part, may contribute to the planning of strategies for utilizing vitamin E isomers against mitochondrial-related diseases such as AD.

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The Role of Vitamin E in Slowing Down Mild Cognitive Impairment: A Narrative Review

Ram Lakhan, Manoj Sharma, Kavita Batra, Frazier B Beatty

Healthcare (Basel) . 2021 Nov 18;9(11):1573. doi: 10.3390/healthcare9111573.

Abstract

With the aging population, dementia emerges as a public health concern. In 2012, the Health and Retirement Study found that 8.8% of adults over 65 years suffered from dementia. The etiopathogenesis and treatment of dementia are not well understood. Antioxidant properties of Vitamin E and its major elements tocopherols and tocotrienols have been reported to be effective in slowing down the progression of dementia from its initial stage of Mild cognitive impairment (MCI). Therefore, the current review aims to explore the role of vitamin E on MCI. A literature search using the key words “Vitamin E, tocopherols, tocotrienols, and mild cognitive impairment” was conducted in MEDLINE (PubMed), CINAHL, and Google Scholar. The inclusion criteria were: (1) articles published in the past ten years; (2) published in English language; (3) published in peer-reviewed journals; and (4) descriptive and epidemiological or evaluation studies. Articles published prior to 2010, focused on other forms of dementia than MCI, grey literature and non-peer-reviewed articles were excluded. A total of 22 studies were included in the narrative synthesis. The results were equivocal. Eleven studies showed some level of the neuroprotective effect of Vitamin E, tocopherols and tocotrienols on the progression of MCI. The mixed results of this review suggest further exploration of the possible protective effects of Vitamin E on the development of dementia. Future studies can be conducted to decipher antioxidant properties of vitamin E and its association with slowing down the cognitive decline.

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Interweaving epilepsy and neurodegeneration: Vitamin E as a treatment approach

Aman B Upaganlawar, Nitu L Wankhede, Mayur B Kale, Mohit D Umare, Aayush Sehgal, Sukhbir Singh, Saurabh Bhatia, Ahmed Al-Harrasi, Agnieszka Najda, Renata Nurzyńska-Wierdak, Simona Bungau, Tapan Behl

Biomed Pharmacother . 2021 Nov;143:112146. doi: 10.1016/j.biopha.2021.112146. Epub 2021 Sep 8.

Abstract

Epilepsy is the most common neurological disorder, affecting nearly 50 million people worldwide. The condition can be manifested either due to genetic predisposition or acquired from acute insult which leads to alteration of cellular and molecular mechanisms. Evaluating the latest and the current knowledge in regard to the mechanisms underlying molecular and cellular alteration, hyperexcitability is a consequence of an imbalanced state wherein enhance excitatory glutamatergic and reduced inhibitory GABAergic signaling is considered to be accountable for seizures associated damage. However, neurodegeneration contributing to epileptogenesis has become increasingly appreciated. The components at the helm of neurodegenerative alterations during epileptogenesis include GABAergic neuronal and receptor changes, neuroinflammation, alteration in axonal transport, oxidative stress, excitotoxicity, and other cellular as well as functional changes. Targeting neurodegeneration with vitamin E as an antioxidant, anti-inflammatory and neuroprotective may prove to be one of the therapeutic approaches useful in managing epilepsy. In this review, we discuss and converse about the seizure-induced episodes as a link for the development of neurodegenerative and pathological consequences of epilepsy. We also put forth a summary of the potential intervention with vitamin E therapy in the management of epilepsy.

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Stress-activated leukocyte 12/15-lipoxygenase metabolite enhances struggle behaviour and tocotrienols relieve stress-induced behaviour alteration

Mototada Shichiri, Noriko Ishida, Yoshinori Aoki, Taisuke Koike, Yoshihisa Hagihara

Free Radic Biol Med . 2021 Nov 1;175:171-183. doi: 10.1016/j.freeradbiomed.2021.08.236. Epub 2021 Aug 30.

Abstract

Stress induces emotional arousal causing anxiety, irritability, exaggerated startle behaviour, and hypervigilance observed in patients with trauma and stress-related mental disorders, including acute stress disorder and post-traumatic stress disorder. Central norepinephrine release promotes stress-induced emotional arousal. However, the regulator of emotional arousal remains unknown. Here, we show that the arachidonate-derived metabolite produced by stress-activated leukocyte 12/15-lipoxygenase is remarkably elevated in the plasma and upregulates the central norepinephrine release, resulting in the enhancement of the struggle behaviour (= escape behaviour) in the tail suspension test. Struggle behaviour is mimicking a symptom of emotional arousal. This stress-induced struggle behaviour was absent in 12/15-lipoxygenase deficient mice; however, intravenous administration of a 12/15-lipoxygenase metabolite to these mice after stress exposure rekindled the struggle behaviour. Furthermore, tocotrienols and geranylgeraniol reduced stress-induced 12/15-lipoxygenase metabolite production and suppressed the struggle behaviour. Our findings indicate that arachidonate-derived 12/15-lipoxygenase metabolite is involved in the regulation of stress-enhanced central norepinephrine release and struggle behaviour. In addition, we propose 12/15-lipoxygenase as a potential therapeutic target for the treatment of emotional arousal observed in stress-related mental disorders.

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An Interactive Review on the Role of Tocotrienols in the Neurodegenerative Disorders

Ruth Naomi, Nurul Husna Shafie, Priyatharisni Kaniappan, Hasnah Bahari

Front Nutr . 2021 Oct 26;8:754086. doi: 10.3389/fnut.2021.754086. eCollection 2021.

Abstract

Neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease, are claimed to be of major concern causing a significant disease burden worldwide. Oxidative stress, mitochondrial dysfunction and nerve damage are the main reasons for the emergence of these diseases. The formation of reactive oxygen species (ROS) is the common chemical molecule that is formed from all these three interdependent mechanisms which is highly reactive toward the neuronal cells. For these reasons, the administration of tocotrienols (T3s), which is a potent antioxidant, is proven to cater to this problem, through in vitro and in vivo investigations. Interestingly, their therapeutic potentials are not only limited to antioxidant property but also to being able to reverse the neuronal damage and act as a shield for mitochondria dysfunction. Thereby, T3s prevents the damage to the neurons. In regards to this statement, in this review, we focused on summarizing and discussing the potential therapeutic role of T3s on Alzheimer’s and Parkinson’s diseases, and their protective mechanisms based on evidence from the in vitro and in vivo studies. However, there is no clinical trial conducted to prove the efficacy of T3s for Alzheimer’s and Parkinson’s subjects. As such, the therapeutic role of T3s for these neurodegenerative disorders is still under debate.

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Enjoy Carefully: The Multifaceted Role of Vitamin E in Neuro-Nutrition

Liesa Regner-Nelke, Christopher Nelke, Christina B Schroeter, Rainer Dziewas, Tobias Warnecke, Tobias Ruck, Sven G Meuth

Int J Mol Sci . 2021 Sep 18;22(18):10087. doi: 10.3390/ijms221810087.

Abstract

Vitamin E is often associated with health benefits, such as antioxidant, anti-inflammatory and cholesterol-lowering effects. These properties make its supplementation a suitable therapeutic approach in neurodegenerative disorders, for example, Alzheimer’s or Parkinson’s disease. However, trials evaluating the effects of vitamin E supplementation are inconsistent. In randomized controlled trials, the observed associations often cannot be substantiated. This could be due to the wide variety of study designs regarding the dosage and duration of vitamin E supplementation. Furthermore, genetic variants can influence vitamin E uptake and/or metabolism, thereby distorting its overall effect. Recent studies also show adverse effects of vitamin E supplementation regarding Alzheimer’s disease due to the increased synthesis of amyloid β. These diverse effects may underline the inhomogeneous outcomes associated with its supplementation and argue for a more thoughtful usage of vitamin E. Specifically, the genetic and nutritional profile should be taken into consideration to identify suitable candidates who will benefit from supplementation. In this review, we will provide an overview of the current knowledge of vitamin E supplementation in neurodegenerative disease and give an outlook on individualized, sustainable neuro-nutrition, with a focus on vitamin E supplementation.

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Plasma antioxidants and risk of dementia in older adults

Manja Koch, Jeremy D Furtado, Héléne Toinét Cronjé, Steven T DeKosky, Annette L Fitzpatrick, Oscar L Lopez, Lewis H Kuller, Kenneth J Mukamal, Majken K Jensen

Alzheimers Dement (N Y) . 2021 Sep 5;7(1):e12208. doi: 10.1002/trc2.12208. eCollection 2021.

Abstract

Introduction: Plant-based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained.

Methods: We measured antioxidants in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer’s disease (AD) during a median of 5.9 years of follow-up. We measured baseline plasma levels of retinol, α-, and γ-tocopherol; zeaxanthin and lutein (combined); beta-cryptoxanthin; cis-lycopene; trans-lycopene; α-carotene; and trans-β-carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist-adjudicated risks of all-cause dementia and AD.

Results: Plasma retinol, α-, and γ-tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or β-carotene, or vitamin E supplements. Higher trans-β-carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans-β-carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α-carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α-carotene: 1.15; 95% CI: 1.02, 1.29).

Discussion: Plasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk.

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The effect of α-tocopherol, α- and γ-tocotrienols on amyloid-β aggregation and disaggregation in vitro

Nor Faeizah Ibrahim, Hamizah Shahirah Hamezah, Daijiro Yanagisawa, Mayumi Tsuji, Yuji Kiuchi, Kenjiro Ono, Ikuo Tooyama

Biochem Biophys Rep . 2021 Sep 10;28:101131. doi: 10.1016/j.bbrep.2021.101131. eCollection 2021 Dec.

Abstract

One of the neuropathological hallmarks of Alzheimer’s disease (AD)-causing neurodegeneration and consequent memory deterioration, and eventually, cognitive decline-is amyloid-β (Aβ) aggregation forming amyloid plaques. Our previous study showed the potential of a tocotrienol-rich fraction-a mixture of naturally occurring of vitamin E analogs-to inhibit Aβ aggregation and restore cognitive function in an AD mouse model. The current study examined the effect of three vitamin E analogs-α-tocopherol (α-TOC), α-tocotrienol (α-T3), and γ-tocotrienol (γ-T3)-on Aβ aggregation, disaggregation, and oligomerization in vitro. Thioflavin T (ThT) assay showed α-T3 reduced Aβ aggregation at 10 μM concentration. Furthermore, both α-T3 and γ-T3 demonstrated Aβ disaggregation, as shown by the reduction of ThT fluorescence. However, α-TOC showed no significant effect. We confirmed the results for ThT assays with scanning electron microscopy imaging. Further investigation in photo-induced cross-linking of unmodified protein assay indicated a reduction in Aβ oligomerization by γ-T3. The present study thus revealed the individual effect of each tocotrienol analog in reducing Aβ aggregation and oligomerization as well as disaggregating preformed fibrils.

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