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Free radicals are molecules that have an unpaired electron, a highly unstable state. Most free radicals react with molecules that contain oxygen to form reactive oxygen species, such as nitric oxide (NO), superoxide (O2-), and hydroxyl (OH-). Free radical damage is associated with many degenerative conditions, including neurological disorders. [5] [6]
Antioxidants inhibit oxidation by free radicals. The term “oxidative stress” refers to the balance of free radicals to antioxidants. Antioxidants include detoxification enzymes, such as superoxide dismutase; vitamins including beta carotene and other carotenoids; vitamins C and E; and nutritional supplements such as coenzyme Q10, cysteine, glutathione, lipoic acid, and melatonin.
In a study published in Neurochemical Research, several parameters indicative of oxidative stress were evaluated in blood from individuals with the sporadic form of amyotrophic lateral sclerosis (SALS) and were compared to healthy controls. Plasma levels of 2-thiobarbituric-reactive substances (TBARS), products of lipid peroxidation, were significantly higher (p < 0.03) in the SALS patients compared to controls. The ratio TBARS/alpha-tocopherol was 47% higher in the SALS individuals than in controls. [77]
Evidence suggests that free radicals in the brain may play a role in the development of age-related neuronal impairments. The increase in the concentration of the pro-inflammatory cytokine (cells which regulate immune responses), interleukin-1 beta (which can cause fever, induce synthesis of acute phase proteins, and initiate metabolic wasting), in aged brain tissue, may also be a contributory factor. This study analyzed changes in enzymatic and non-enzymatic antioxidant levels, in parallel with interleukin-1 beta concentration, in cortical brain tissue prepared from young and aged rats. Results showed an age-related increase in the activity of superoxide dismutase. An age-related decrease in the concentrations of vitamin E and C was also shown. These observations, coupled with age-related increases in lipid peroxidation and interleukin-1 beta concentration show a compromised antioxidant defense in cortex of aged rats. These negative changes were not observed in cortical tissue prepared from rats fed on a diet supplemented with vitamin E and C for 12 weeks. [78]
Glutathione, an antioxidant and molecule used to conjugate toxins in the body, may be beneficial for ALS. A decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. [79]
One study showed that estradiol, a naturally occurring estrogen that has been produced semi-synthetically, protects spinal motor neurons from excitotoxic insults in vitro, and may have application as a treatment for ALS. The dose of estradiols required for motor neuron protection was greatly reduced by co-administration with glutathione. [80] A study of the role of estrogen in ALS, however, found that there was no difference in survival in those patients taking estrogen compared to those not on the medication. [81]
The genetic form of ALS is autosomal dominant with a defect on SOD1, the gene encoding superoxide dismutase. Superoxide is an oxygen molecule with an extra electron. Superoxide dismutase, or SOD, is an antioxidant enzyme that adds hydrogen to the superoxide molecule to convert it into stable oxygen plus hydrogen peroxide (H2O2). [82]
There is evidence that the point mutations in superoxide dismutase, which are associated with amyotrophic lateral sclerosis, may contribute to mitochondrial dysfunction. [7] A recent study showed that treatment with superoxide dismutase improves neuromuscular dysfunction and morphological changes in wobbler mouse motor neuron disease. [83]
Superoxide dismutase is under Phase One scientific investigation for its use in ALS. [50] [84]
Zinc supplementation should be considered in addition to superoxide dismutase. A recent study showed that the loss of zinc from SOD was sufficient to induce apoptosis (programmed cell death) in cultured motor neurons. When replete with zinc, SOD was not toxic. Both protected motor neurons from growth factor withdrawal. [85]
Mitochondrial superoxide dismutase requires manganese, while the cytoplasmic (cellular) form requires copper and zinc. Patients with familial ALS possess a defective gene that decreases cytoplasmic SOD by 40%. [5]
N-acetyl-L-cysteine (NAC) is an antioxidant agent that reduces free radical damage.
In a study at Massachusetts General Hospital and Harvard Medical School, N-acetyl-L-cysteine (NAC) was used as preventative treatment in transgenic mice with a superoxide dismutase mutation. NAC supplementation resulted in significantly prolonged survival and delayed onset of motor impairment when compared to control mice. The authors encouraged further research and clinical trials for ALS treatment with NAC. [86]
One study published in the Journal of Neuroscience (USA) studied the effects of N-acetyl-L-cysteine (NAC) on mice with mutation that caused lower motoneuron degeneration with associated skeletal muscle atrophy (wobbler mice). This mutation shares some of the clinical features of amyotrophic lateral sclerosis (ALS). Litters of wobbler mice were given a 1% solution of the glutathione precursor NAC in their drinking water for a period of 9 weeks. Functional and neurological examination of these animals revealed that wobbler mice treated with NAC exhibited (1) a significant reduction in motor neuron loss and elevated glutathione peroxidase levels within the cervical spinal cord, (2) increased axon caliber in the medial facial nerve, (3) increased muscle mass and muscle fiber area in the triceps and flexor carpi ulnaris muscles, and (4) increased functional efficiency of the forelimbs, as compared with untreated wobbler littermates. These data suggest that reactive oxygen species may be involved in the degeneration of motor neurons in wobbler mice and demonstrate that oral administration of NAC effectively reduces the degree of motor degeneration in wobbler mice. [87]
Another study published in the Journal Neurology Science (Netherlands) described how 36 patients with sporadic amyotrophic lateral sclerosis were treated with an array of antioxidants in addition to their prescription medications. Their customary prescription sequence was N-acetylcysteine (NAC); vitamins C and E; N-acetylmethionine (NAM); and dithiothreitol (DTT) or its isomer dithioerythritol (DTE). Patients with a history of heavy exposure to metal were also given meso 2,3-dimercaptosuccinic acid (DMSA). NAC, NAM, DTT, and DTE were administered by subcutaneous injection or by mouth or by both routes, the other vitamins and DMSA by mouth alone. Comparison of survival in the treated group and in a cohort of untreated historical controls, disclosed a median survival of 3.4 years (95% confidence interval: 3.0-4.2) in the treated and of 2.8 (95% confidence interval 2.2-3.1) years in the control patients. This difference may be explained by self-selection of the highly motivated treated group and by its initial survival of diagnosis for an average of 8.5 months before onset of treatment. The authors conclude that antioxidants neither seem to harm ALS patients, nor do they seem to prolong survival. [88]
A recent paper has proposed that vitamin C deficiency may be the underlying mechanism for the development of ALS. Three mechanisms were proposed. First, superoxide radicals are a common substrate for both superoxide dismutase and ascorbate. Second, brain-cell ascorbate release is coupled with glutamate uptake. Third, there is evidence supporting the vitamin C deficient (scurvy) guinea pig as a model for amyotrophic lateral sclerosis. [89]
Vitamin C also plays an important role in the transmission of signals between neurons. Glutamate and aspartate (Vitamin C) are the two main excitatory neurotransmitters in the brain with glutamate being responsible for 75% of it. One possible hypothesis would be that excessive reliance on glutamate may be due to a deficiency of vitamin C. [3]
To help protect against respiratory dysfunction, 600 mg of N-acetylcysteine (NAC) and 1000 mg of vitamin C, 3 times a day, are suggested.
Vitamin E is a potent antioxidant. Deficiency is associated with progressive neurologic deterioration. Several studies in the 1940s described improvement in ALS patients when supplemented with alpha-tocopherol, the natural form of Vitamin E. [90] [91] [92]
A recent study in Neuroscience Letters reported remarkably low levels of alpha-tocopherol quinone in the cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. [93]
The authors of one paper on vitamin E stated that “dietary supplementation with vitamin E delays onset of clinical disease and slows progression in the transgenic mice model but does not prolong survival.” [94]
One author notes that vitamin E is beneficial only for some patients with ALS and recommends further investigation. [95]
Alpha-lipoic acid is a potent antioxidant that is especially effective in preventing diabetic neuropathy. [96] [97] [98]
Alpha-lipoic acid has been shown to stimulate nerve growth factor synthesis and secretion in mouse astroglial cells. Astrocytes are cells which support the structure of the nervous tissue. [99]
Therefore, a dose of 250 mg 3 times a day of alpha-lipoic acid to protect the neurons affected by ALS is suggested.
Continue to Part 5 of the ALS Article
© 2002