ascorbic-acid and Amyotrophic-Lateral-Sclerosis

Prior research has suggested the possible role of oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS). Prospective data examining dietary antioxidants such carotenoids and vitamin C are limited.. Risk of ALS associated with carotenoid and vitamin C intake was investigated in 5 prospective cohorts: the National Institutes of Health-Association of American Retired Persons Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, the Health Professionals Follow-up Study (HPFS), and the Nurses Health Study (NHS). ALS deaths were documented using the National Death Index, and confirmed nonfatal ALS cases were included from HPFS and NHS. A total of 1,153 ALS deaths occurred among 1,100,910 participants (562,942 men; 537,968 women). Participants were categorized into cohort-specific quintiles of intake for dietary variables. We applied Cox proportional hazards regression to calculate cohort-specific risk ratios (RRs), and pooled results using random-effects methods.. A greater total major carotenoids intake was associated with a reduced risk of ALS (pooled, multivariate-adjusted RR for the highest to the lowest quintile = 0.75, 95% confidence interval [CI] = 0.61-0.91, p for trend = 0.004). Individually, higher dietary intakes of β-carotene and lutein were inversely associated with ALS risk. The pooled multivariate RRs comparing the highest to the lowest quintile for β-carotene and lutein were 0.85 (95% CI = 0.64-1.13, p for trend = 0.03) and 0.79 (95% CI = 0.64-0.96, p for trend = 0.01), respectively. Lycopene, β-cryptoxanthin, and vitamin C were not associated with reduced risk of ALS.. Consumption of foods high in carotenoids may help prevent or delay onset of ALS.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Antioxidants; Ascorbic Acid; Carotenoids; Female; Follow-Up Studies; Humans; Male; Middle Aged; Oxidative Stress; Proportional Hazards Models; Prospective Studies; Risk Factors

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.

Topics: Adult; Age Factors; Aged; Amyotrophic Lateral Sclerosis; Antioxidants; Ascorbic Acid; Cohort Studies; Confidence Intervals; Cross-Sectional Studies; Dietary Supplements; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Prospective Studies; Retrospective Studies; Risk; Risk Factors; Sex Factors; Surveys and Questionnaires; Vitamin E; Vitamins

Vitamin C is one of the most common supplements taken by people with ALS. As an antioxidant, it has a plausible mechanism for slowing disease progression and there are some flawed pre-clinical studies and case reports suggesting benefit. However, a small human trial showed no benefit. Given this negative trial, we do not currently advise vitamin C as an ALS treatment.

Topics: Amyotrophic Lateral Sclerosis; Ascorbic Acid; Clinical Trials as Topic; Dietary Supplements; Humans; Treatment Outcome; Vitamins

Topics: Amyotrophic Lateral Sclerosis; Antioxidants; Ascorbic Acid; Carotenoids; Female; Humans; Male

Topics: Amyotrophic Lateral Sclerosis; Antioxidants; Ascorbic Acid; Carotenoids; Female; Humans; Male

Ferrous iron, released from iron deposits in the motor cortex and other brain regions of amyotrophic lateral sclerosis (ALS) patients, participates in the Fenton reaction in cerebrospinal fluid (CSF) alongside H(2)O(2), which is continuously released by neuronal cells. In vivo, the production of notoriously reactive hydroxyl radicals via this reaction could lead to the progression of the disease. Herein, we have examined the effect of ascorbate and uric acid on the production of hydroxyl radicals in CSF from both sporadic ALS patients and control subjects. Electron paramagnetic resonance spectroscopy identified ascorbyl radicals in CSF from ALS patients whereas it was undetectable in control CSF. The addition of H(2)O(2) to the CSF from ALS patients provoked further formation of ascorbyl radicals and the formation of hydroxyl radicals ex vivo. The hydroxyl addition of uric acid to CSF from ALS patients diminished the production of hydroxyl radicals. In conclusion, there are clear differences between the roles of the two examined radical scavengers in the CSF of ALS patients indicating that the use of ascorbate could have unfavourable effects in ALS patients.

Topics: Amyotrophic Lateral Sclerosis; Ascorbic Acid; Cerebrospinal Fluid; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Humans; Uric Acid

Pathophysiological mechanisms involved in amyotrophic lateral sclerosis (ALS) are complex and none has identified reliable markers useful in routine patient evaluation. The aim of this study was to analyze the CSF of patients with ALS by (1)H NMR (Nuclear Magnetic Resonance) spectroscopy in order to identify biomarkers in the early stages of the disease, and to evaluate the biochemical factors involved in ALS.. CSF samples were collected from patients with ALS at the time of diagnosis and from patients without neurodegenerative diseases. One and two-dimensional (1)H NMR analyses were performed and metabolites were quantified by the ERETIC method. We compared the concentrations of CSF metabolites between both groups. Finally, we performed principal component (PCA) and discriminant analyses.. Fifty CSF samples from ALS patients and 44 from controls were analyzed. We quantified 17 metabolites including amino-acids, organic acids, and ketone bodies. Quantitative analysis revealed significantly lower acetate concentrations (p = 0.0002) in ALS patients compared to controls. Concentration of acetone trended higher (p = 0.015), and those of pyruvate (p = 0.002) and ascorbate (p = 0.003) were higher in the ALS group. PCA demonstrated that the pattern of analyzed metabolites discriminated between groups. Discriminant analysis using an algorithm of 17 metabolites revealed that patients were accurately classified 81.6% of the time.. CSF screening by NMR spectroscopy could be a useful, simple and low cost tool to improve the early diagnosis of ALS. The results indicate a perturbation of glucose metabolism, and the need to further explore cerebral energetic metabolism.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Amyotrophic Lateral Sclerosis; Ascorbic Acid; Case-Control Studies; Discriminant Analysis; Female; Humans; Magnetic Resonance Spectroscopy; Male; Metabolomics; Middle Aged; Principal Component Analysis; Protons; Pyruvates

There has been little interest in the role of nutrition in the prevention of amyotrophic lateral sclerosis (ALS). We investigated the relationship between dietary intake of vegetables, fruit, and antioxidants and the risk of ALS in Japan.. Between 2000 and 2004, we recruited 153 ALS patients aged 18-81 years with disease duration of 3 years within the study period in accordance with El Escorial World Federation of Neurology criteria. Three hundred and six gender- and age-matched controls were randomly selected from the general population. Information on dietary factors was collected using a validated self-administered diet history questionnaire.. A higher consumption of all fruits and vegetables and fruit alone in the highest quartiles was associated with a statistically significantly reduced risk of ALS. Although not statistically significant, a beneficial association between intake of all vegetables, green and yellow vegetables and other vegetables and ALS was found. No statistically significant dose-response relationship was observed between intake of beta-carotene, vitamin C and vitamin E and the risk of ALS.. Our findings suggest that higher intake of food rich in antioxidants such as fruit and vegetables confer protection against the development of ALS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Antioxidants; Ascorbic Acid; beta Carotene; Diet; Female; Fruit; Humans; Japan; Male; Middle Aged; Surveys and Questionnaires; Vegetables; Vitamin E; Young Adult

We have compared plasma redox status of coenzyme Q-10 in 20 sporadic amyotrophic lateral sclerosis (sALS) patients with those in 20 healthy age/sex-matched controls. A significant increase in the oxidized form of coenzyme Q-10 (sALS=109.3+/-95.2 nM; controls=23.3+/-7.5 nM, P=0.0002) and in the ratio of oxidized form of coenzyme Q-10 to total coenzyme Q-10 (%CoQ-10) (sALS=12.0+/-9.3%; controls=3.2+/-0.9%, P<0.0001) were observed. Moreover, %CoQ-10 correlated significantly with the duration of illness (rho=0.494, P=0.0315). Our finding suggests systemic oxidative stress in the pathogenesis of sALS.

Topics: Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Ascorbic Acid; Bilirubin; Case-Control Studies; Chromatography, High Pressure Liquid; Coenzymes; Female; Follow-Up Studies; Humans; Male; Middle Aged; Oxidation-Reduction; Statistics, Nonparametric; Time Factors; Ubiquinone; Uric Acid

A "gain-of-function" toxic property of mutant Cu-Zn superoxide dismutase 1 (SOD1) is involved in the pathogenesis of some familial cases of amyotrophic lateral sclerosis (ALS). Expression of a mutant form of the human SOD1 gene in mice causes a degeneration of motor neurons, leading to progressive muscle weakness and hindlimb paralysis. Transgenic mice overexpressing a mutant human SOD1 gene (G93A-SOD1) were used to examine the mitochondrial involvement in familial ALS. We observed a decrease in mitochondrial respiration in brain and spinal cord of the G93A-SOD1 mice. This decrease was significant only at the last step of the respiratory chain (complex IV), and it was not observed in transgenic wild-type SOD1 and nontransgenic mice. Interestingly, this decrease was evident even at a very early age in mice, long before any clinical symptoms arose. The effect seemed to be CNS specific, because no decrease was observed in liver mitochondria. Differences in complex IV respiration between brain mitochondria of G93A-SOD1 and control mice were abolished when reduced cytochrome c was used as an electron donor, pinpointing the defect to cytochrome c. Submitochondrial studies showed that cytochrome c in the brain of G93A-SOD1 mice had a reduced association with the inner mitochondrial membrane (IMM). Brain mitochondrial lipids, including cardiolipin, had increased peroxidation in G93A-SOD1 mice. These results suggest a mechanism by which mutant SOD1 can disrupt the association of cytochrome c with the IMM, thereby priming an apoptotic program.

Topics: Aging; Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Ascorbic Acid; Brain; Cytochromes c; Disease Models, Animal; Electron Transport; Electron Transport Complex IV; Female; Humans; Intracellular Membranes; Lipid Peroxidation; Male; Mice; Mice, Transgenic; Mitochondria; Nitric Oxide Synthase; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1; Tetramethylphenylenediamine

Oxidative stress, linked to Abeta-lipid interactions, plays a pathogenetic role in Alzheimer's disease. We investigated modifications of lipid peroxidation products in plasma of 52 AD patients, 42 healthy controls and 16 patients with amyotrophic lateral sclerosis, a neurodegenerative disease where oxidative stress also plays a pathogenetic role. Final lipid peroxidation products were measured in plasma by thiobarbituric acid reactive substances (TBARS) assay before and after ex vivo oxidative stress catalysed by copper. There were no significant changes at basal conditions, but after copper-induced oxidation TBARS levels were higher in AD patients (19.0 microM +/- 2.2) versus both controls (5.2 microM +/- 0.8, p<0.001) and ALS patients (7.6 microM +/- 2.1, p<0.01). Stimulated TBARS levels were significantly higher in mild and moderate AD (p<0.0001) with respect to controls, but not in severe AD patients, with a significant inverse correlation between disease severity and lipid peroxidation (p<0.005, r2=0.21). Treatment of a subgroup (13) of mild and moderate AD patients with vitamin C and E for three months decreased plasma lipoperoxidation susceptibility by 60%. Thus, oxidative stress, expressed as ex vivo susceptibility to lipid peroxidation, appears to be an early phenomenon, probably related to AD pathogenetic mechanisms.

Topics: Aged; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Apolipoproteins E; Ascorbic Acid; Case-Control Studies; Copper; Female; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidation-Reduction; Polymorphism, Genetic; Severity of Illness Index; Thiobarbituric Acid Reactive Substances; Vitamin E

One of the hypotheses regarding the pathogenesis of familial ALS (FALS) is a copper-mediated oxidative toxicity derived from the mutant Cu, Zn-superoxide dismutase (SOD1). We have previously demonstrated the efficacy of the combined treatment with a copper chelator (trientine) and an antioxidant (ascorbate) on the disease expression of the FALS-linked mutated SOD1 transgenic mice. Here, we investigated the efficacy of trientine or ascorbate alone on FALS mice when administered before or after the onset of the disease. The mice with a high dose of trientine or ascorbate administered before the onset survived significantly longer than the control. In the combined treatment with a high dose of trientine and ascorbate initiated before the onset, survival lengthened and the motor function of the mice remained more significantly than the control. None of the treatments affected the mean age of the onset, and none of the agents administered after the onset prolonged survival. These findings suggest that better outcomes may be expected by the administration of these agents at the preonset stage of the disease, and the combination of the agents acting on different sites might be useful in preserving the motor performance in FALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Ascorbic Acid; Chelating Agents; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Male; Mice; Mice, Transgenic; Superoxide Dismutase; Superoxide Dismutase-1; Survival Rate; Treatment Outcome; Trientine

The involvement of mitochondrial dysfunction promoting neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), has been suggested. Histopathological and biochemical mitochondrial abnormalities have been reported in both sporadic and familial patients and suggest the contention that mitochondria may play a key role promoting ALS. Animal models of ALS provide a unique opportunity to study this incurable and fatal human disease. In the present study we tested the hypothesis that alterations in mitochondrial physiology occur in the brain of wobbler mice. No significant difference was found in the respiratory control index or adenosine diphosphate/oxygen ratio values between isolated mitochondria of wobbler and control mice. When pyruvate and malate were used as substrates, oxygen consumption was decreased significantly by approximately 33% in mitochondria isolated from wobbler mouse brain compared to controls. Oxygen consumption in the presence of ascorbate and N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) was decreased significantly by approximately 21% in wobbler brain mitochondria compared to controls, which suggests impairment in the function of complex IV. These findings are the first demonstration of mitochondrial respiratory chain dysfunction in the brain of the wobbler mouse.

Topics: Amyotrophic Lateral Sclerosis; Animals; Ascorbic Acid; Brain; Cell Respiration; Disease Models, Animal; Electron Transport; Malates; Mice; Mice, Neurologic Mutants; Mitochondria; Oxygen Consumption; Pyruvic Acid

Mutations in copper,zinc-superoxide dismutase (SOD) have been implicated in familial amyotrophic lateral sclerosis (FALS). We have investigated the breakdown of S-nitrosothiols by wild-type (WT) SOD and two common FALS mutants, alanine-4 valine (A4V) SOD and glycine-37 arginine (G37R) SOD. In the presence of glutathione, A4V SOD and G37R SOD catalyzed S-nitrosoglutathione breakdown three times more efficiently than WT SOD. Indeed, A4V SOD catabolized GSNO more efficiently than WT SOD throughout the physiological range of GSH concentrations. Moreover, a variety of additional S-nitrosothiols were catabolized more readily by A4V SOD than by WT SOD. Initial rate data for fully reduced WT SOD and A4V SOD, and data using ascorbic acid as the reductant, suggest that FALS mutations in SOD may influence the efficiency of reduction of the copper center by glutathione. We have identified a potentially toxic gain of function of two common FALS mutations that may contribute to neurodegeneration in FALS.

Topics: Amyotrophic Lateral Sclerosis; Ascorbic Acid; Copper; Humans; Mutation; Nitroso Compounds; S-Nitrosoglutathione; S-Nitrosothiols; Serum Albumin, Bovine; Superoxide Dismutase; Zinc

Calcineurin is a serine/threonine phosphatase involved in a wide range of cellular responses to calcium mobilizing signals. Previous evidence supports the notion of the existence of a redox regulation of this enzyme, which might be relevant for neurodegenerative processes, where an imbalance between generation and removal of reactive oxygen species could occur. In a recent work, we have observed that calcineurin activity is depressed in two models for familial amyotrophic lateral sclerosis (FALS) associated with mutations of the antioxidant enzyme Cu,Zn superoxide dismutase (SOD1), namely in neuroblastoma cells expressing either SOD1 mutant G93A or mutant H46R and in brain areas from G93A transgenic mice. In this work we report that while wild-type SOD1 has a protective effect, calcineurin is oxidatively inactivated by mutant SOD1s in vitro; this inactivation is mediated by reactive oxygen species and can be reverted by addition of reducing agents. Furthermore, we show that calcineurin is sensitive to oxidation only when it is in an 'open', calcium-activated conformation, and that G93A-SOD1 must have its redox-active copper site available to substrates in order to exert its pro-oxidant properties on calcineurin. These findings demonstrate that both wild-type and mutant SOD1s can interfere directly with calcineurin activity and further support the possibility of a relevant role for calcineurin-regulated biochemical pathways in the pathogenesis of FALS.

Topics: Aerobiosis; Amyotrophic Lateral Sclerosis; Antioxidants; Ascorbic Acid; Calcineurin; Calcium; Copper; Dithiothreitol; Enzyme Activation; Humans; Nerve Degeneration; Oxidation-Reduction; Point Mutation; Reactive Oxygen Species; Recombinant Proteins; Superoxide Dismutase

We previously reported that the common toxic gain-of-function in various mutant copper-zinc superoxide dismutases (SOD1) seen in patients with familial amyotrophic lateral sclerosis (ALS) was an abnormal copper release from the enzyme protein. In this study, trientine and ascorbate, known to have a beneficial effect in an animal model of Wilson disease, were administered to transgenic mice overexpressing a mutated human SOD1 (G93A). The onset of neurological signs in the treated group was significantly delayed compared with that in the control group, and the time to reach total paralysis in the treated group was delayed as well. Since the agents used in this study cause low toxicity in animals and humans, this treatment may be a good candidate for clinical application.

Topics: Amyotrophic Lateral Sclerosis; Animals; Ascorbic Acid; Chelating Agents; Copper; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Humans; Mice; Mice, Transgenic; Superoxide Dismutase; Survival Analysis; Trientine

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease in which upper and lower motoneurons progressively deteriorate and die. Neuronal damage is most evident in the lower central nervous system, and death generally occurs following central respiratory failure. Proposed and demonstrated mechanisms for amyotrophic lateral sclerosis are diverse, and include altered superoxide dismutase and neurofilament proteins, autoimmune attack, and hyperglutamatergic activity. However, they do not account for the late onset of the disease, its earlier onset in males, and the differential vulnerability of neurons located in the brainstem and spinal cord. It is proposed here that, within the context of a specific defect such as altered superoxide dismutase, age-dependent decline in ascorbate availability triggers the disease. A role for ascorbate, which is found in millimolar levels in neurons, is suggested by a number of consistencies: 1) superoxide radicals being a common substrate for superoxide dismutase and ascorbate; 2) a close association between central nervous system ascorbate levels and injury tolerance; 3) a steady decline in ascorbate plasma levels and cellular availability with age; 4) plasma ascorbate levels being lower in males; 5) an association of ascorbate release with motor activity in central nervous system regions, in vivo; 6) the coupling of brain-cell ascorbate release with glutamate uptake; 7) possible roles for ascorbate modulation of N-methyl-D-aspartate receptor activity; 9) the ability of ascorbate to prevent peroxynitrite anion formation; and 10) evidence supporting the scorbutic guinea pig as a model for amyotrophic lateral sclerosis. Emphasis is placed on the probable competition between superoxide dismutase and ascorbate within the context of a primary defect of metal-binding or metal access in high-concentration proteins such as superoxide dismutase and human heavy neurofilaments. Finally, distinct features of alpha-motoneuronal physiology suggest that cell physiological characteristics such as high metabolic activity and extensive calcium dynamics may render neurons differentially vulnerable in amyotrophic lateral sclerosis.

Topics: Amyotrophic Lateral Sclerosis; Animals; Ascorbic Acid; Biological Availability; Central Nervous System; Humans; Models, Neurological; Nerve Degeneration; Superoxide Dismutase

The aim of the present study was to report the levels of ascorbic acid in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) and the effectiveness of ascorbic acid homeostasis in the central nervous system. Plasma and CSF ascorbic acid levels were measured by high performance liquid chromatography in 19 ALS patients, 17 AD patients and 15 controls. No statistically significant difference was found between patients and controls. However, wide fluctuations of plasma concentrations were found to result in relatively stable CSF levels, by appropriate adjustments of CSF/plasma ratio. It appears that in normal subjects and in the disease under study, this ratio reflects the activity of the choroid plexus ascorbate transporter.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Analysis of Variance; Ascorbic Acid; Biomarkers; Case-Control Studies; Chi-Square Distribution; Female; Homeostasis; Humans; Least-Squares Analysis; Male; Middle Aged

Topics: Amyotrophic Lateral Sclerosis; Ascorbic Acid; Brain Neoplasms; Cerebrospinal Fluid Proteins; Cerebrovascular Disorders; Humans; Methods; Nucleic Acids; Spectrophotometry; Ultraviolet Rays