Vitamin E intake and risk of amyotrophic lateral sclerosis

Department of Nutrition, Harvard School of Public Health, 655 Huntington Avenue, Building 2, Boston, MA 02115, USA.
Annals of Neurology (Impact Factor: 9.98). 01/2005; 57(1):104-10. DOI: 10.1002/ana.20316
Source: PubMed


Oxidative stress may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). We therefore examined prospectively whether individuals who regularly use supplements of the antioxidant vitamins E and C have a lower risk of ALS than nonusers. The study population comprised 957,740 individuals 30 years of age or older participating in the American Cancer Society's Cancer Prevention Study II. Information on vitamin use was collected at time of recruitment in 1982; participants then were followed up for ALS deaths from 1989 through 1998 via linkage with the National Death Index. During the follow-up, we documented 525 deaths from ALS. Regular use of vitamin E supplements was associated with a lower risk of dying of ALS. The age- and smoking-adjusted relative risk was 0.99 (95% confidence interval [CI], 0.69-1.41) among occasional users, 0.59 (95% CI, 0.36-0.96) in regular users for less than 10 years, and 0.38 (95% CI, 0.16-0.92) in regular users for 10 years or more as compared with nonusers of vitamin E (p for trend = 0.004). In contrast, no significant associations were found for use of vitamin C or multivitamins. These results suggest that vitamin E supplementation could have a role in ALS prevention.

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    • "We first analyzed use of vitamin E, the most potent naturally occurring scavenger of reactive oxygen and nitrogen species known (Tucker and Townsend, 2005). Extensive studies in ALS patients and mice models have shown, however, that vitamin E application in vivo is not capable of significantly prolonging survival (Gurney et al., 1996; Desnuelle et al., 2001; Ascherio et al., 2005; Graf et al., 2005) These disappointing results are likely related to the findings that vitamin E poorly penetrates the blood-brain barrier, leading to insufficient doses of this anti-oxidant in the central nervous system; IC50 of vitamin E is between 1.5 and 59 μM while ventricular CSF concentration of this vitamin was found at 0.114 μM (reviewed in Barber and Shaw, 2010). Here we opted to use Trolox, a water-soluble vitamin E analog that neutralizes ROS (Ghiselli et al., 1995; Khaldy et al., 2000; Barber et al., 2009; Distelmaier et al., 2012). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder caused by dysfunction and degeneration of motor neurons. Multiple disease-causing mutations, including in the genes for SOD1 and TDP-43, have been identified in ALS. Astrocytes expressing mutant SOD1 are strongly implicated in the pathogenesis of ALS: we have shown that media conditioned by astrocytes carrying mutant SOD1(G93A) contains toxic factor(s) that kill motoneurons by activating voltage-sensitive sodium (Na v ) channels. In contrast, a recent study suggests that astrocytes expressing mutated TDP43 contribute to ALS pathology, but do so via cell-autonomous processes and lack non-cell-autonomous toxicity. Here we investigate whether astrocytes that express diverse ALS-causing mutations release toxic factor(s) that induce motoneuron death, and if so, whether they do so via a common pathogenic pathway. We exposed primary cultures of wild-type spinal cord cells to conditioned medium derived from astrocytes (ACM) that express SOD1 (ACM-SOD1(G93A) and ACM-SOD1(G86R)) or TDP43 (ACM-TDP43(A315T)) mutants; we show that such exposure rapidly (within 30-60 min) increases dichlorofluorescein (DCF) fluorescence (indicative of nitroxidative stress) and leads to extensive motoneuron-specific death within a few days. Co-application of the diverse ACMs with anti-oxidants Trolox or esculetin (but not with resveratrol) strongly improves motoneuron survival. We also find that co-incubation of the cultures in the ACMs with Na v channel blockers (including mexiletine, spermidine, or riluzole) prevents both intracellular nitroxidative stress and motoneuron death. Together, our data document that two completely unrelated ALS models lead to the death of motoneuron via non-cell-autonomous processes, and show that astrocytes expressing mutations in SOD1 and TDP43 trigger such cell death through a common pathogenic pathway that involves nitroxidative stress, induced at least in part by Na v channel activity.
    Full-text · Article · Feb 2014 · Frontiers in Cellular Neuroscience
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    • "Numerous reports have suggested that all types of vitamin E scavenge reactive oxygen species and protect cells and organs against oxidative stress as their common potent characteristic [5] [6] [7]. Furthermore, recent epidemiological and clinical studies suggest that vitamin E is effective in oxidative stress-related neurodegenerative disorders such as Parkinson's disease (PD) [8] [9] [10], Alzheimer's disease [11], and amyotrophic lateral sclerosis [12]. However, other clinical studies have failed to confirm the efficacy of vitamin E members, especially αTOC, in the treatment of these diseases [13] [14] [15]. "
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    ABSTRACT: Tocotrienols (T3s) are members of the vitamin E family, have antioxidant properties, and are promising candidates for neuroprotection in the pathogenesis of neurodegenerative disorders such as Parkinson’s disease (PD). However, whether their antioxidant capacities are required for their cytoprotective activity remains unclear. In this regard, the antioxidant-independent cytoprotective activity of T3s has received considerable attention. Here, we investigated the signaling pathways that are induced during T3-dependent cytoprotection of human neuroblastoma SH-SY5Y cells, as these cells are used to model certain elements of PD. T3s were cytoprotective against MPP+ and other PD-related toxicities. γT3 and δT3 treatment led to marked activation of the PI3K/Akt signaling pathway. Furthermore, we identified estrogen receptor (ER) β as an upstream mediator of PI3K/Akt signaling following γT3/δT3 stimulation. Highly purified γT3/δT3 bound to ERβ directly in vitro, and knockdown of ERβ in SH-SY5Y cells abrogated both γT3/δT3-dependent cytoprotection and Akt phosphorylation. Since membrane-bound ERβ was important for the signal-related cytoprotective effects of γT3/δT3, we investigated receptor-mediated caveola formation as a candidate for the early events of signal transduction. Knockdown of caveolin-1 and/or caveolin-2 prevented the cytoprotective effects of γT3/δT3, but did not affect Akt phosphorylation. This finding suggests that T3s and, in particular, γT3/δT3, exhibit not only antioxidant effects but also a receptor signal-mediated protective action following ERβ/PI3K/Akt signaling. Furthermore, receptor-mediated caveola formation is an important event during the early steps following T3 treatment.
    Full-text · Article · Jan 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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    • "Contents lists available at SciVerse ScienceDirect journal homepage: development of ALS to 0.38 [12]. Also riluzole, the only approved neuroprotective treatment for ALS, is an antiglutamatergic agent which also has antioxidant properties [13]. "
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    ABSTRACT: Compelling evidence indicates that oxidative stress contributes to motor neuron injury in amyotrophic lateral sclerosis (ALS), but anti-oxidant therapies have not yet achieved therapeutic benefit in the clinic. The nuclear erythroid 2-related-factor 2 (Nrf2) transcription factor is a key regulator of an important neuroprotective response by driving the expression of multiple cytoprotective genes via its interaction with the anti-oxidant response element (ARE). Dysregulation of the Nrf2-ARE system has been identified in ALS models and the human disease. Taking the Nrf2-ARE pathway as an attractive therapeutic target for neuroprotection in ALS, we aimed to identify CNS penetrating, small molecule activators of Nrf2-mediated transcription in a library of 2000 drugs and natural products. Compounds were screened extensively for Nrf2 activation, anti-oxidant and neuroprotective properties in vitro. S[+]apomorphine, a receptor-inactive enantiomer of the clinically approved dopamine-receptor agonist (R[-]apomorphine), was identified as a non-toxic Nrf2 activating molecule. In vivo S[+]apomorphine demonstrated CNS penetrance, Nrf2 induction and significant attenuation of motor dysfunction in the SOD1(G93A) transgenic mouse model of ALS. S[+] apomorphine also reduced pathological oxidative stress and improved survival following an oxidative insult in fibroblasts from ALS patients. This molecule emerges as a promising candidate for evaluation as a potential neuroprotective agent in ALS patients in the clinic.
    Full-text · Article · Apr 2013 · Free Radical Biology and Medicine
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