Motor Neuron Disease, also known as ALS, is a progressive, degenerative, neuromuscular disease that progresses quickly and destroys nerve cells in the brain and spinal cord. Once these nerve cells (neurons) are destroyed they can no longer send messages to the muscles and control is lost over voluntary muscle movement
The exact cause of motor neuron cell death is still unknown but the condition is most likely multifactorial and aggravated by a number of underlying health irregularities. Scientists are investigating a number of theories, including free radical damage from oxidative stress, calcium dysregulation, glutamate toxicity, mitochondrial dysfunction and even viral infections as possible causes. It is believed that these factors may work synergistically to cause and advance the disease. Heavy metals, inflammation and environmental agents are also possible factors to consider. 1 An optimal regimen of nutrients and supplements for individuals with MND may be able to delay the effects of these contributing factors and slow the progression of the disease, therefore reducing its symptoms. Conventional medicine, which as yet has been unsuccessful in treating MND, also attempts to lessen symptoms by slowing progression. Currently however, one pharmaceutical drug approved for MND patients has been shown to extend life span by only two months. 2
A comprehensive integrative approach should be considered to address the underlying defects of the disease. There is a central role of defective mitochondrial energy production, and the resulting increased levels of free radicals, in the pathogenesis of various neurodegenerative diseases. 3 Defects in energy metabolism may therefore contribute to both excitetoxicity and oxidative damage. Due to this impaired antioxidant activity in MND patients, treatment reducing oxidative stress may slow the course of the disease 4 and should be the first port of call.
A recent study in humans indicated that vitamin E may significantly delay symptom onset and slow disease progression in MND because of its antioxidant properties. 5 Vitamin E helps protect cell membranes against lipid peroxidation.6 Selenium supplementation may increase the amount of vitamin E in the blood and increase activity of glutathione among MND patients. Ginkgo biloba also has antioxidant properties 7 and may promote healthy mitochondrial function. 8 During an in vitro study, Gingko biloba was found to protect against glutamate-induced excitotoxicity. 9
Zinc is involved in many physiological processes in the body. Changes in zinc metabolism that lead to neurodegeneration can occur during times of oxidative stress.10 Zinc supplementation has potential benefit due to its integral role in the function of SOD. SOD is an antioxidant enzyme that reduces oxidative stress and can play a key role in assisting MND. Mutations in SOD have decreased ability to bind to zinc and may contribute to MND. 11 It is important to note that large doses of zinc inhibit copper absorption so therefore the dosage in supplementing zinc and the synergistic interaction of copper and zinc needs to be considered in terms of predicting the toxic or neuroprotective effects. 12
There is promise in using co-enzyme Q10 for treating MND. Co-enzyme Q10 is a critical component of the electron transport chain for proper mitochondrial function and acts as an antioxidant.13 A study found that oral supplementation significantly reduces weight loss, delays motor deficits, and extends life span in MND.14
Acetyl-l-Carnitine has been shown to inhibit mitochondrial damage and apoptosis. 15 It could also have neurotrophic activity and increase glutathione concentrations. 16 Early oral administration of acetyl-l-carnitine may significantly delay symptom onset, prolong motor function and extend survival rates. The effects of acetyl-l-carnitine are increased when administered in conjunction with alpha- lipoic acid.17
Alpha-lipoic acid, also an antioxidant may increase intracellular levels of glutathione 18, and chelate metals such as iron and copper.19 Furthermore, alpha-lipoic acid has been shown to protect cells against glutamate-induced excitotoxicity. 20 Alpha-lipoic acid may therefore significant delay impaired motor performance as well as increase survival. 21
Dietary supplementation with amino acids may have some beneficial effects on the course of the disease.22 The use of creatine has also been encouraging. Creatine aids in the formation of ATP, which is the primary source of cellular energy. In multiple studies, creatine was shown to provide protective mechanisms against neurodegenerative diseases by helping to stabilize mitochondrial membranes and mitochondrial energy-transfer complexes.23 Creatine may also reduce oxidative stress, increase glutamate uptake and improve motor performance. 24 In addition, a small preliminary study found that creatine supplementation helps reduce the loss of muscle strength in MND patients.25 Ultra high doses of vitamin B12 may also improve or slow muscle wasting, which is common during the later stages of the disease. 26 The observation that patients with MND may have elevated plasma homocysteine levels has encouraged the use of the B vitamins, particularly folic acid and vitamin B12.
More recent data has suggested that curcumin (an extract from turmeric) may help improve calcium status in muscle tissue and reduce inflammatory processes. 27, 28 While human studies are needed to confirm these results, preclinical evidence suggests that curcumin could be useful in MND. Vinpocetine and Resveratrol may also inhibit the flow of calcium into cells, which is associated with glutamate-induced cell toxicity.29, 37 This is similar to the mechanism of action of riluzole, the only FDA-approved drug used to treat MND.
Evidence suggests that MND associated nerve cell death is partly due to low levels of the antioxidant glutathione, which protects cells from toxins and free radicals. 30 Lower glutathione peroxidase activity has been shown in plasma and cerebrospinal fluid of MND patients. 31 Glutathione peroxidase, catalase, and superoxide dismutase (SOD) are all antioxidants synthesized by the body that counteract reactive oxygen species (ROS) damage. Toxicity resulting from mutated SOD is implicated in the pathophysiology in familial MND. Increasing glutathione levels could therefore help prevent free radical damage to cells. 32 The glutathione precursor N-acetyl cysteine (NAC) boosts blood levels of glutathione and oral administration decreases motor neuron loss, improves muscle mass, and increases survival time and motor performance. 33
Epigallocatechin gallate (EGCG) is a major catechin found in green tea. It displays antioxidant, anti- inflammatory 34 and mild metal chelating properties. 35 EGCG also significantly delays symptom onset and prolongs life span. Pycnogenol also has antioxidant properties 36, as well as protective effects against glutamate excitotoxicity. 9 Procyanidins, which can be found in grape seeds, cranberries, blueberries, almonds, and peanuts, demonstrate potent antioxidant properties. 36 Pycnogenol is a common complementary therapy option among MND patients. 6
Dehydroepiandrosterone (DHEA) is a naturally occurring steroid hormone and in several in vitro studies, DHEA has been shown to protect against glutamate-induced toxicity 38 although only a few studies have examined DHEA in MND patients.
The benefits of aggressive nutritional support in affecting the course of disease and survival are well documented. Nutritional supplements that prevent free radical damage, stabilize mitochondrial membranes, or stimulate electron transport chain complexes may be of tremendous value in MND patients.
- Mano Y, Takayanagi T, et al. [Amyotrophic lateral sclerosis and mercury—preliminary report]. Rinsho Shinkeigaku . 1990;30(11):1275–1277.
- Lacomblez L, Bensimon G, et al. A confirmatory dose-ranging study of riluzole in ALS. ALS/Riluzole Study Group-II. Neurology. 1996;47(6 Suppl 4):S242–S250.
- Rosenfeld J, Ellis A. Nutrition and Dietary Supplements in Motor Neuron Disease.Physical Medicine and Rehabilitation Clinics of North America, Volume 19, Issue 3, August 2008, Pages 573-589
- Apostolski S, Marinkovic Z, et al. Glutathione peroxidase in amyotrophic lateral sclerosis: the effects of selenium supplementation. J Environ Pathol Toxicol Oncol . 1998;17(3–4):325–329.
- Ascherio AJ, Weisskopf MG, et al. Vitamin E intake and risk of amyotrophic lateral sclerosis. Ann Neurol . 2005;57(1):104–110.
- Cameron A, Rosenfeld J. Nutritional issues and supplements in amyotrophic lateral sclerosis and other neurodegenerative disorders. Curr Opin Clin Nutr Metab Care. 2002;5(6):631–643.
- Ernst E. The risk-benefit profile of commonly used herbal therapies: Ginkgo, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto, and Kava. Ann Intern Med. 2002;136(1):42–53.
- Fosslien E. Mitochondrial medicine—molecular pathology of defective oxidative phosphorylation. Ann Clin Lab Sci. 2001;31(1):25–67.
- Kobayashi MS, Han D, Packer L. Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity. Free Radic Res. 2000;32(2):115–124.
- Cuajungco MP, Lees GJ. Zinc metabolism in the brain: relevance to human neurodegenerative disorders. Neurobiol Dis. 1997;4(3–4):137–169.
- Banci L, Felli IC, et al. Direct detection of hydrogen bonds in monomeric superoxide dismutase: biological implications. Biochemistry. 2002;41(9):2913–2920.
- Ermilova IP, Ermilov VB, et al. Protection by dietary zinc in ALS mutant G93A SOD transgenic mice. Neurosci Lett . 2005;379(1):42–46.
- Galpern WR, Cudkowicz ME. Coenzyme Q treatment of neurodegenerative diseases of aging. Mitochondrion. 2007;7 suppl:S146–S153.
- Beal MF. Coenzyme Q10 as a possible treatment for neurodegenerative diseases. Free Radic Res . 2002;36(4):455–460.
- Carta A, Calvani M, et al. Acetyl-L-carnitine and Alzheimer’s disease: pharmacological considerations beyond the cholinergic sphere. Ann N Y Acad Sci. 1993;695:324–326.
- Thal LJ, Calvani M, et al. A 1-year controlled trial of acetyl-1 -carnitine in early-onset AD. Neurology. 2000;55(6):805–810.
- Hagen TM, Liu J, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A. 2002;99(4):1870–1875.
- Zhang WJ, Frei B. Alpha lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. Faseb J . 2001;15(13): 2423– 2432.
- Pioro EP. Antioxidant therapy in ALS. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(Suppl 4):5–12; discussion 13–15.
- Muller U, Krieglstein J. Prolonged pretreatment with alpha-lipoic acid protects cultured neurons against hypoxic, glutamate-, or iron-induced injury. J Cereb Blood Flow Metab. 1995;15(4):624–630.
- Andreassen OA, Dedeoglu A, Friedlich A, et al. Effects of an inhibitor of poly(ADP-ribose) polymerase, desmethylselegiline, trientine, and lipoic acid in transgenic ALS mice. Experimental Neurology. 2001;168(2):419–424.
- Palma A, de Carvalho M, et al. Biochemical characterization of plasma in amyotrophic lateral sclerosis: amino acid and protein composition. Amyotoph Lateral Scler Other Motor Neuron Disord . 2005;6(2):104–110
- Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev. 2001;53(2):161–176.
- Tarnopolsky MA, Beal MF. Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol. 2001;49(5):561–574.
- Mazzini L, Balzarini C, et al. Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. J Neurol Sci. 2001;191(1–2):139–144.
- Kaji R, Kodama M, et al. Effect of ultrahigh-dose methylcobalamin on compound muscle action potentials in amyotrophic lateral sclerosis: a double-blind controlled study. Muscle Nerve . 1998;21(12):1775–1778.
- Logan-Smith MJ, Lockyer PJ, et al. Curcumin, a molecule that inhibits the Ca2+-ATPase of sarcoplasmic reticulum but increases the rate of accumulation of Ca2+. J Biol Chem. 2001;276(50):46905–46911.
- Sumbilla C, Lewis D, et al. The slippage of the Ca2+ pump and its control by anions and curcumin in skeletal and cardiac sarcoplasmic reticulum. J Biol Chem. 2002;277(16):13900– 13906.
- Wu SN. Large-conductance Ca2+- activated K+ channels: physiological role and pharmacology. Curr Med Chem . 2003;10(8):649–661.
- Chi L, Ke Y, et al. Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo. Neuroscience. 9 Feb 2007;1443):991-1003
- Chio A, Cucatto A, Terreni AA, Schiffer D. Reduced glutathione in amyotrophic lateral sclerosis: an open, crossover, randomized trial. Italian Journal of Neurological Sciences. 1998;19(6):363–366.
- Exner R, Wessner B, et al. Therapeutic potential of glutathione. Wien Klin Wochenschr. 2000;112(14):610–616.
- Andreassen OA, Dedeoglu A, et al. N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Neuroreport. 2000;11(11):2491–2493.
- Hong JT, Ryu SR, et al. Neuroprotective effect of green tea extract in experimental ischemia- reperfusion brain injury. Brain Res Bull. 2000;53(6):743–749.
- Levites Y, Youdim MB , et al. Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures. Biochem Pharmacol. 2002;63(1):21–29.
- Packer L, Rimbach G, et al. Antioxidant activity and biologic properties of a procyanidin-rich extract from pine (Pinus maritima) bark, pycnogenol. Free Radic Biol Med. 1999;27(5– 6):704–724.
- Wu SN, Li HF, et al. Vinpocetine-enhanced stimulation of calcium-activated potassium currents in rat pituitary GH3 cells. Biochem Pharmacol . 2001;61(7):877–892.
- Lapchak PA, Araujo DM. Preclinical development of neurosteroids as neuroprotective agents for the treatment of neurodegenerative diseases. Int Rev Neurobiol. 2001;46:379–397.