Skip to main content

Advertisement

SpringerLink
Log in

Lipoic Acid and Other Antioxidants as Therapies for Multiple Sclerosis

  • Multiple Sclerosis and Related Disorders (J Graves, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Abstract

Oxidative stress (OS), when oxidative forces outweigh endogenous and nutritional antioxidant defenses, contributes to the pathophysiology of multiple sclerosis (MS). Evidence of OS is found during acute relapses, in active inflammatory lesions, and in chronic, longstanding plaques. OS results in both ongoing inflammation and neurodegeneration. Antioxidant therapies are a rational strategy for people with MS with all phenotypes and disease durations.

Purpose of review

To understand the function of OS in health and disease, to examine the contributions of OS to MS pathophysiology, and to review current evidence for the effects of selected antioxidant therapies in people with MS (PwMS) with a focus on lipoic acid (LA).

Recent findings

Studies of antioxidant interventions in both animal and in vivo models result in reductions in serum markers of OS and increases in levels and activity of antioxidant enzymes. Antioxidant trials in PwMS, while generally underpowered, detect short-term improvements in markers of OS and antioxidant defenses, and to a lesser extent, in clinical symptoms (fatigue, depression). The best evidence to date is a 2-year trial of LA in secondary progressive MS which demonstrated a significant reduction of whole-brain atrophy and trend toward improvement in walking speed.

Summary

Antioxidant therapy is a promising approach to treat MS across the spectrum and duration of disease. Rigorous and well-powered trials are needed to determine their therapeutic benefits.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci. 2003;206(2):165–71.

    Article  CAS  PubMed  Google Scholar 

  2. Geurts JJ, Calabrese M, Fisher E, Rudick RA. Measurement and clinical effect of grey matter pathology in multiple sclerosis. Lancet Neurol. 2012;11(12):1082–92. https://doi.org/10.1016/s1474-4422(12)70230-2.

    Article  PubMed  Google Scholar 

  3. Baldassari LE, Fox RJ. Therapeutic advances and challenges in the treatment of progressive multiple sclerosis. Drugs. 2018;78:1549–66. https://doi.org/10.1007/s40265-018-0984-5.

    Article  CAS  PubMed  Google Scholar 

  4. Ortiz GG, Pacheco-Moises FP, Bitzer-Quintero OK, Ramirez-Anguiano AC, Flores-Alvarado LJ, Ramirez-Ramirez V, et al. Immunology and oxidative stress in multiple sclerosis: clinical and basic approach. Clin Dev Immunol. 2013;2013:708659–14. https://doi.org/10.1155/2013/708659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gilgun-Sherki Y, Melamed E, Offen D. The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol. 2004;251(3):261–8. https://doi.org/10.1007/s00415-004-0348-9.

    Article  CAS  PubMed  Google Scholar 

  6. Adamczyk B, Adamczyk-Sowa M. New insights into the role of oxidative stress mechanisms in the pathophysiology and treatment of multiple sclerosis. Oxidative Med Cell Longev. 2016;2016:1973834–18. https://doi.org/10.1155/2016/1973834.

    Article  CAS  Google Scholar 

  7. Kidd PM. Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management. Altern Med Rev. 2005;10(4):268–93.

    PubMed  Google Scholar 

  8. Staniek K, Nohl H. Are mitochondria a permanent source of reactive oxygen species? Biochim Biophys Acta. 2000;1460(2–3):268–75.

    Article  CAS  PubMed  Google Scholar 

  9. Floyd RA, Hensley K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging. 2002;23(5):795–807.

    Article  CAS  PubMed  Google Scholar 

  10. Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem. 2005;12(10):1161–208.

    Article  CAS  PubMed  Google Scholar 

  11. Bouayed J, Bohn T. Exogenous antioxidants-double-edged swords in cellular redox state: health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxidative Med Cell Longev. 2010;3(4):228–37. https://doi.org/10.4161/oxim.3.4.12858.

    Article  Google Scholar 

  12. Schipper HM. Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Res Rev. 2004;3(3):265–301. https://doi.org/10.1016/j.arr.2004.02.001.

    Article  CAS  PubMed  Google Scholar 

  13. Wagener FA, Volk HD, Willis D, Abraham NG, Soares MP, Adema GJ, et al. Different faces of the heme-heme oxygenase system in inflammation. Pharmacol Rev. 2003;55(3):551–71. https://doi.org/10.1124/pr.55.3.5.

    Article  CAS  PubMed  Google Scholar 

  14. Shichiri M. The role of lipid peroxidation in neurological disorders. J Clin Biochem Nutr. 2014;54(3):151–60. https://doi.org/10.3164/jcbn.14-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 2016;7:11624. https://doi.org/10.1038/ncomms11624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. •• Dodson M, de la Vega MR, Cholanians AB, Schmidlin CJ, Chapman E, Zhang DD. Modulating NRF2 in disease: timing is everything. Ann Rev Pharmacol Toxicol. 2018. https://doi.org/10.1146/annurev-pharmtox-010818-021856 Overview of the NRF2 signalling pathway including regulation and dowstream targets. Raises important issues regarding timing of measurement of effects based on physiological and pathological contexts.

    Article  CAS  PubMed  Google Scholar 

  17. Caglayan B, Kilic E, Dalay A, Altunay S, Tuzcu M, Erten F, et al. Allyl isothiocyanate attenuates oxidative stress and inflammation by modulating Nrf2/HO-1 and NF-kappaB pathways in traumatic brain injury in mice. Mol Biol Rep. 2018;46:241–50. https://doi.org/10.1007/s11033-018-4465-4.

    Article  CAS  PubMed  Google Scholar 

  18. Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012;341(1):274–84. https://doi.org/10.1124/jpet.111.190132.

    Article  CAS  PubMed  Google Scholar 

  19. • Mailloux RJ. Mitochondrial antioxidants and the maintenance of cellular hydrogen peroxide levels. Oxidative Med Cell Longev. 2018;2018:7857251. https://doi.org/10.1155/2018/7857251 Review of mitochondrial ROS homeostasis and mitochondrial antioxidant properties in mammals.

    Article  Google Scholar 

  20. Cross AH, Manning PT, Stern MK, Misko TP. Evidence for the production of peroxynitrite in inflammatory CNS demyelination. J Neuroimmunol. 1997;80(1–2):121–30.

    Article  CAS  PubMed  Google Scholar 

  21. Cross AH, Manning PT, Keeling RM, Schmidt RE, Misko TP. Peroxynitrite formation within the central nervous system in active multiple sclerosis. J Neuroimmunol. 1998;88(1–2):45–56.

    Article  CAS  PubMed  Google Scholar 

  22. Langemann H, Kabiersch A, Newcombe J. Measurement of low-molecular-weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis. Eur Neurol. 1992;32(5):248–52. https://doi.org/10.1159/000116835.

    Article  CAS  PubMed  Google Scholar 

  23. Witte ME, Bo L, Rodenburg RJ, Belien JA, Musters R, Hazes T, et al. Enhanced number and activity of mitochondria in multiple sclerosis lesions. J Pathol. 2009;219(2):193–204. https://doi.org/10.1002/path.2582.

    Article  PubMed  Google Scholar 

  24. van Horssen J, Schreibelt G, Drexhage J, Hazes T, Dijkstra CD, van der Valk P, et al. Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med. 2008;45(12):1729–37. https://doi.org/10.1016/j.freeradbiomed.2008.09.023.

    Article  CAS  PubMed  Google Scholar 

  25. Hill KE, Zollinger LV, Watt HE, Carlson NG, Rose JW. Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage. J Neuroimmunol. 2004;151(1–2):171–9. https://doi.org/10.1016/j.jneuroim.2004.02.005.

    Article  CAS  PubMed  Google Scholar 

  26. Haider L, Fischer MT, Frischer JM, Bauer J, Hoftberger R, Botond G, et al. Oxidative damage in multiple sclerosis lesions. Brain. 2011;134(Pt 7):1914–24. https://doi.org/10.1093/brain/awr128.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mirshafiey A, Mohsenzadegan M. Antioxidant therapy in multiple sclerosis. Immunopharmacol Immunotoxicol. 2009;31(1):13–29. https://doi.org/10.1080/08923970802331943.

    Article  CAS  PubMed  Google Scholar 

  28. Van Der Goes A, Brouwer J, Hoekstra K, Roos D, Van Den Berg TK, Dijkstra CD. Reactive oxygen species are required for the phagocytosis of myelin by macrophages. J Neuroimmunol. 1998;92(1–2):67–75. https://doi.org/10.1016/S0165-5728(98)00175-1.

    Article  PubMed  Google Scholar 

  29. van Horssen J, Witte ME, Schreibelt G, de Vries HE. Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta. 2011;1812(2):141–50. https://doi.org/10.1016/j.bbadis.2010.06.011.

    Article  CAS  PubMed  Google Scholar 

  30. Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain. 2012;135(Pt 3):886–99. https://doi.org/10.1093/brain/aws012.

    Article  PubMed  PubMed Central  Google Scholar 

  31. van Meeteren ME, Teunissen CE, Dijkstra CD, van Tol EA. Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005;59(12):1347–61. https://doi.org/10.1038/sj.ejcn.1602255.

    Article  CAS  PubMed  Google Scholar 

  32. Mann CL, Davies MB, Boggild MD, Alldersea J, Fryer AA, Jones PW, et al. Glutathione S-transferase polymorphisms in MS: their relationship to disability. Neurology. 2000;54(3):552–7.

    Article  CAS  PubMed  Google Scholar 

  33. de Sousa CV, Sales MM, Rosa TS, Lewis JE, de Andrade RV, Simoes HG. The antioxidant effect of exercise: a systematic review and meta-analysis. Sports Med. 2017;47(2):277–93. https://doi.org/10.1007/s40279-016-0566-1.

    Article  PubMed  Google Scholar 

  34. Swank RL, Goodwin J. Review of MS patient survival on a Swank low saturated fat diet. Nutrition. 2003;19(2):161–2.

    Article  CAS  PubMed  Google Scholar 

  35. Huntley A, Ernst E. Complementary and alternative therapies for treating multiple sclerosis symptoms: a systematic review. Complement Ther Med. 2000;8(2):97–105. https://doi.org/10.1054/ctim.2000.0366.

    Article  CAS  PubMed  Google Scholar 

  36. Salinthone S, Yadav V, Bourdette DN, Carr DW. Lipoic acid: a novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS. Endocr Metab Immune Disord Drug Targets. 2008;8(2):132–42.

    Article  CAS  PubMed  Google Scholar 

  37. Snell EE, Strong FM, Peterson WH. Growth factors for bacteria: fractionation and properties of an accessory factor for lactic acid bacteria. Biochem J. 1937;31(10):1789–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Reed LJ, Gunsalus IC, Schnakenberg GHF, Soper QF, Boaz HE, Kern SF, et al. Isolation, characterization and structure of α-lipoic Acid1. J Am Chem Soc. 1953;75(6):1267–70. https://doi.org/10.1021/ja01102a001.

    Article  CAS  Google Scholar 

  39. Rosenberg HRCR. Effect of α-lipoic acid on vitamin C and vitamin E deficiencies. Arch Biochem Biophys. 1959;80(1):86–93. https://doi.org/10.1016/0003-9861(59)90345-5.

    Article  CAS  Google Scholar 

  40. Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol. 1997;29(3):315–31.

    Article  CAS  PubMed  Google Scholar 

  41. Dietrich M, Helling N, Hilla A, Heskamp A, Issberner A, Hildebrandt T et al. Early alpha-lipoic acid therapy protects from degeneration of the inner retinal layers and vision loss in an experimental autoimmune encephalomyelitis-optic neuritis model. J Neuroinflamm. 2018;15(1). https://doi.org/10.1186/s12974-018-1111-y.

  42. Seifar F, Khalili M, Khaledyan H, Amiri Moghadam S, Izadi A, Azimi A et al. alpha-Lipoic acid, functional fatty acid, as a novel therapeutic alternative for central nervous system diseases: a review. Nutr Neurosci. 2017;1–11. https://doi.org/10.1080/1028415x.2017.1386755.

    Article  PubMed  Google Scholar 

  43. Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta. 2009;1790(10):1149–60. https://doi.org/10.1016/j.bbagen.2009.07.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Marracci GH, Jones RE, McKeon GP, Bourdette DN. Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J Neuroimmunol. 2002;131(1–2):104–14. https://doi.org/10.1016/S0165-5728(02)00269-2.

    Article  CAS  PubMed  Google Scholar 

  45. Takaishi N, Yoshida K, Satsu H, Shimizu M. Transepithelial transport of alpha-lipoic acid across human intestinal Caco-2 cell monolayers. J Agric Food Chem. 2007;55(13):5253–9. https://doi.org/10.1021/jf063624i.

    Article  CAS  PubMed  Google Scholar 

  46. Prasad PD, Wang H, Kekuda R, Fujita T, Fei YJ, Devoe LD, et al. Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate. J Biol Chem. 1998;273(13):7501–6.

    Article  CAS  PubMed  Google Scholar 

  47. Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med. 1997;22(1–2):359–78.

    Article  CAS  PubMed  Google Scholar 

  48. Panigrahi M, Sadguna Y, Shivakumar BR, Kolluri SV, Roy S, Packer L, et al. alpha-Lipoic acid protects against reperfusion injury following cerebral ischemia in rats. Brain Res. 1996;717(1–2):184–8.

    Article  CAS  PubMed  Google Scholar 

  49. Chng HT, New LS, Neo AH, Goh CW, Browne ER, Chan EC. Distribution study of orally administered lipoic acid in rat brain tissues. Brain Res. 2009;1251:80–6. https://doi.org/10.1016/j.brainres.2008.11.025.

    Article  CAS  PubMed  Google Scholar 

  50. Schupke H, Hempel R, Peter G, Hermann R, Wessel K, Engel J, et al. New metabolic pathways of alpha-lipoic acid. Drug Metab Dispos. 2001;29(6):855–62.

    CAS  PubMed  Google Scholar 

  51. Yadav V, Marracci GH, Munar MY, Cherala G, Stuber LE, Alvarez L, et al. Pharmacokinetic study of lipoic acid in multiple sclerosis: comparing mice and human pharmacokinetic parameters. Mult Scler. 2010;16(4):387–97. https://doi.org/10.1177/1352458509359722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. • Bittner F, Murchison C, Koop D, Bourdette D, Spain R. Lipoic acid pharmacokinetics at baseline and 1 year in secondary progressive MS. Neurol Neuroimmunol NeuroInflamm. 2017;4(5). https://doi.org/10.1212/NXI.0000000000000380. This study confirmed high inter-subject variability in the Spain 2017 study, and newly reported high intra-subject variability between evaluations.

    Article  Google Scholar 

  53. Bast A, Haenen GR. Lipoic acid: a multifunctional antioxidant. Biofactors. 2003;17(1–4):207–13.

    Article  CAS  PubMed  Google Scholar 

  54. Goraca A, Huk-Kolega H, Piechota A, Kleniewska P, Ciejka E, Skibska B. Lipoic acid - biological activity and therapeutic potential. Pharmacol Rep: PR. 2011;63(4):849–58.

    Article  CAS  PubMed  Google Scholar 

  55. Takechi R, Pallebage-Gamarallage MM, Lam V, Giles C, Mamo JC. Nutraceutical agents with anti-inflammatory properties prevent dietary saturated-fat induced disturbances in blood-brain barrier function in wild-type mice. J Neuroinflammation. 2013;10:73. https://doi.org/10.1186/1742-2094-10-73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Shay KP, Michels AJ, Li W, Kong AN, Hagen TM. Cap-independent Nrf2 translation is part of a lipoic acid-stimulated detoxification stress response. Biochim Biophys Acta. 2012;1823(6):1102–9. https://doi.org/10.1016/j.bbamcr.2012.04.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schreibelt G, Musters RJP, Reijerkerk A, De Groot LR, Van Der Pol SMA, Hendrikx EML, et al. Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity. J Immunol. 2006;177(4):2630–7. https://doi.org/10.4049/jimmunol.177.4.2630.

    Article  CAS  PubMed  Google Scholar 

  58. • George JD, Kim E, Spain R, Bourdette D, Salinthone S. Effects of lipoic acid on migration of human B cells and monocyte-enriched peripheral blood mononuclear cells in relapsing remitting multiple sclerosis. J Neuroimmunol. 2018;315:24–7. https://doi.org/10.1016/j.jneuroim.2017.12.009 This study confirmed results found in EAE, demonstrating reduced migratory capacity in PBMCs and B cells in people with RRMS and treated with LA.

    Article  CAS  PubMed  Google Scholar 

  59. Schillace RV, Pisenti N, Pattamanuch N, Galligan S, Marracci GH, Bourdette DN, et al. Lipoic acid stimulates cAMP production in T lymphocytes and NK cells. Biochem Biophys Res Commun. 2007;354(1):259–64. https://doi.org/10.1016/j.bbrc.2006.12.195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Salinthone S, Yadav V, Schillace RV, Bourdette DN, Carr DW. Lipoic acid attenuates inflammation via cAMP and protein kinase A signaling. PloS One. 2010;5(9). https://doi.org/10.1371/journal.pone.0013058.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Fiedler SE, Yadav V, Kerns AR, Tsang C, Markwardt S, Kim E, et al. Lipoic acid stimulates cAMP production in healthy control and secondary progressive MS subjects. Mol Neurobiol. 2018;55(7):6037–49. https://doi.org/10.1007/s12035-017-0813-y.

    Article  CAS  PubMed  Google Scholar 

  62. Yadav V, Marracci G, Lovera J, Woodward W, Bogardus K, Marquardt W, et al. Lipoic acid in multiple sclerosis: a pilot study. Mult Scler. 2005;11(2):159–65. https://doi.org/10.1191/1352458505ms1143oa.

    Article  CAS  PubMed  Google Scholar 

  63. • Chaudhary P, Marracci G, Galipeau D, Pocius E, Morris B, Bourdette D. Lipoic acid reduces inflammation in a mouse focal cortical experimental autoimmune encephalomyelitis model. J Neuroimmunol. 2015;289:68–74. https://doi.org/10.1016/j.jneuroim.2015.10.011 This study demonstrates the anti-inflammatory effects of LA on cortical lesions, an area difficult to study in humans, however, does not investigate the antioxidant effects per se.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Morini M, Roccatagliata L, Dell'Eva R, Pedemonte E, Furlan R, Minghelli S, et al. α-Lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2004;148(1–2):146–53. https://doi.org/10.1016/j.jneuroim.2003.11.021.

    Article  CAS  PubMed  Google Scholar 

  65. Khalili M, Azimi A, Izadi V, Eghtesadi S, Mirshafiey A, Sahraian MA, et al. Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial. Neuroimmunomodulation. 2014;21(6):291–6. https://doi.org/10.1159/000356145.

    Article  CAS  PubMed  Google Scholar 

  66. Chaudhary P, Marracci GH, Bourdette DN. Lipoic acid inhibits expression of ICAM-1 and VCAM-1 by CNS endothelial cells and T cell migration into the spinal cord in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2006;175(1–2):87–96. https://doi.org/10.1016/j.jneuroim.2006.03.007.

    Article  CAS  PubMed  Google Scholar 

  67. Wang KC, Tsai CP, Lee CL, Chen SY, Lin GJ, Yen MH, et al. α-Lipoic acid enhances endogenous peroxisome-proliferator-activated receptor-γ to ameliorate experimental autoimmune encephalomyelitis in mice. Clin Sci. 2013;125(7):329–40. https://doi.org/10.1042/CS20120560.

    Article  CAS  Google Scholar 

  68. Jones RE, Moes N, Zwickey H, Cunningham CL, Gregory WL, Oken B. Treatment of experimental autoimmune encephalomyelitis with alpha lipoic acid and associative conditioning. Brain Behav Immun. 2008;22(4):538–43. https://doi.org/10.1016/j.bbi.2007.10.017.

    Article  CAS  PubMed  Google Scholar 

  69. Khalili M, Eskandari G, Ghajarzadeh M, Azimi A, Eghtesadi S, Sahraian MA, et al. Lipoic acid and multiple sclerosis: a randomized controlled clinical trial. Curr Top Nutraceutical Res. 2012;10(2):95–100.

    CAS  Google Scholar 

  70. Khalili M, Eghtesadi S, Mirshafiey A, Eskandari G, Sanoobar M, Sahraian MA, et al. Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial. Nutr Neurosci. 2014;17(1):16–20. https://doi.org/10.1179/1476830513y.0000000060.

    Article  CAS  PubMed  Google Scholar 

  71. Khalili M, Soltani M, Moghadam SA, Dehghan P, Azimi A, Abbaszadeh O. Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients: a randomized clinical trial. Electron Physician. 2017;9(7):4899–905. https://doi.org/10.19082/4899.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Riccio P, Rossano R, Larocca M, Trotta V, Mennella I, Vitaglione P, et al. Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: a pilot study. Exp Biol Med. 2016;241(6):620–35. https://doi.org/10.1177/1535370215618462.

    Article  CAS  Google Scholar 

  73. •• Spain R, Powers K, Murchison C, Heriza E, Winges K, Yadav V et al. Lipoic acid in secondary progressive MS. Neurology: Neuroimmunology and NeuroInflammation. 2017;4(5). https://doi.org/10.1212/NXI.0000000000000374. The longest randomized clinical trial of lipoic acid in people with secondary progressive MS to date demonstrating a reduction in whole-brain atrophy but not clinical outcomes.

    Article  PubMed  Google Scholar 

  74. •• Plemel JR, Juzwik CA, Benson CA, Monks M, Harris C, Ploughman M. Over-the-counter anti-oxidant therapies for use in multiple sclerosis: a systematic review. Mult Scler. 2015;21(12):1485–95. https://doi.org/10.1177/1352458515601513 Comprehensive review of all pre-clinical and clinical studies up to October, 1, 2013, of over-the counter oantioxidant therapies in MS.

    Article  CAS  PubMed  Google Scholar 

  75. Mohammadzadeh Honarvar N, Harirchian MH, Abdolahi M, Abedi E, Bitarafan S, Koohdani F, et al. Retinyl palmitate supplementation modulates T-bet and interferon gamma gene expression in multiple sclerosis patients. J Mol Neurosci. 2016;59(3):360–5. https://doi.org/10.1007/s12031-016-0747-2.

    Article  CAS  PubMed  Google Scholar 

  76. Bitarafan S, Saboor-Yaraghi A, Sahraian MA, Nafissi S, Togha M, Beladi Moghadam N, et al. Impact of vitamin A supplementation on disease progression in patients with multiple sclerosis. Arch Iran Med. 2015;18(7):435–40.

    PubMed  Google Scholar 

  77. • Bitarafan S, Saboor-Yaraghi A, Sahraian MA, Soltani D, Nafissi S, Togha M, et al. Effect of vitamin A supplementation on fatigue and depression in multiple sclerosis patients: a double-blind placebo-controlled clinical trial. Iran J Allergy Asthma Immunol. 2016;15(1):13–9 This study is notable for the large size (n = 101) and relatively long duration (6 months) allowing for detection of a clinical benefit.

    PubMed  Google Scholar 

  78. Guan JZ, Guan WP, Maeda T. Vitamin E administration erases an enhanced oxidation in multiple sclerosis. Can J Physiol Pharmacol. 2018;96(11):1181–3. https://doi.org/10.1139/cjpp-2018-0246.

    Article  CAS  PubMed  Google Scholar 

  79. Sanoobar M, Eghtesadi S, Azimi A, Khalili M, Jazayeri S, Reza GM. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with relapsing-remitting multiple sclerosis. Int J Neurosci. 2013;123(11):776–82. https://doi.org/10.3109/00207454.2013.801844.

    Article  CAS  PubMed  Google Scholar 

  80. Sanoobar M, Eghtesadi S, Azimi A, Khalili M, Khodadadi B, Jazayeri S, et al. Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial. Nutr Neurosci. 2015;18(4):169–76. https://doi.org/10.1179/1476830513Y.0000000106.

    Article  CAS  PubMed  Google Scholar 

  81. Sanoobar M, Dehghan P, Khalili M, Azimi A, Seifar F. Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: a double blind randomized clinical trial. Nutr Neurosci. 2016;19(3):138–43. https://doi.org/10.1179/1476830515y.0000000002.

    Article  CAS  PubMed  Google Scholar 

  82. Shinto L, Marracci G, Mohr DC, Bumgarner L, Murchison C, Senders A, et al. Omega-3 fatty acids for depression in multiple sclerosis: a randomized pilot study. PLoS One. 2016;11(1):e0147195. https://doi.org/10.1371/journal.pone.0147195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zandi-Esfahan S, Fazeli M, Shaygannejad V, Hasheminia J, Badihian S, Aghayerashti M, et al. Evaluating the effect of adding fish oil to Fingolimod on TNF-alpha, IL1beta, IL6, and IFN-gamma in patients with relapsing-remitting multiple sclerosis: a double-blind randomized placebo-controlled trial. Clin Neurol Neurosurg. 2017;163:173–8. https://doi.org/10.1016/j.clineuro.2017.10.004.

    Article  PubMed  Google Scholar 

  84. Sorto-Gomez TE, Ortiz GG, Pacheco-Moises FP, Torres-Sanchez ED, Ramirez-Ramirez V, Macias-Islas MA, et al. Effect of fish oil on glutathione redox system in multiple sclerosis. Am J Neurodegener Dis. 2016;5(2):145–51.

    PubMed  PubMed Central  Google Scholar 

  85. Kouchaki E, Afarini M, Abolhassani J, Mirhosseini N, Bahmani F, Masoud SA, et al. High-dose omega-3 fatty acid plus vitamin D3 supplementation affects clinical symptoms and metabolic status of patients with multiple sclerosis: a randomized controlled clinical trial. J Nutr. 2018;148(8):1380–6. https://doi.org/10.1093/jn/nxy116.

    Article  PubMed  Google Scholar 

  86. Adamczyk-Sowa M, Sowa P, Adamczyk J, Niedziela N, Misiolek H, Owczarek M, et al. Effect of melatonin supplementation on plasma lipid hydroperoxides, homocysteine concentration and chronic fatigue syndrome in multiple sclerosis patients treated with interferons-beta and mitoxantrone. J Physiol Pharmacol. 2016;67(2):235–42.

    CAS  PubMed  Google Scholar 

  87. Adamczyk-Sowa M, Pierzchala K, Sowa P, Polaniak R, Kukla M, Hartel M. Influence of melatonin supplementation on serum antioxidative properties and impact of the quality of life in multiple sclerosis patients. J Physiol Pharmacol. 2014;65(4):543–50.

    CAS  PubMed  Google Scholar 

  88. Roostaei T, Sahraian MA, Hajeaghaee S, Gholipour T, Togha M, Siroos B, et al. Impact of melatonin on motor, cognitive and neuroimaging indices in patients with multiple sclerosis. Iran J Allergy Asthma Immunol. 2015;14(6):589–95.

    PubMed  Google Scholar 

  89. Drake MJ, Canham L, Cotterill N, Delgado D, Homewood J, Inglis K, et al. Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS). BMC Neurol. 2018;18(1):107. https://doi.org/10.1186/s12883-018-1114-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Schipper HM, Arnold D, Grand'Maison F, Melmed C, Moore F, Levental M, et al. Tolerability and safety of combined glatiramer acetate and N-acetylcysteine in relapsing-remitting multiple sclerosis. Clin Neuropharmacol. 2015;38(4):127–31. https://doi.org/10.1097/wnf.0000000000000090.

    Article  CAS  PubMed  Google Scholar 

  91. Gonsette RE, Sindic C, D'Hooghe MB, De Deyn PP, Medaer R, Michotte A, et al. Boosting endogenous neuroprotection in multiple sclerosis: the ASsociation of Inosine and Interferon beta in relapsing-remitting Multiple Sclerosis (ASIIMS) trial. Mult Scler. 2010;16(4):455–62. https://doi.org/10.1177/1352458509360547.

    Article  CAS  PubMed  Google Scholar 

  92. • Munoz Garcia D, Midaglia L, Martinez Vilela J, Marin Sanchez M, Lopez Gonzalez FJ, Arias Gomez M, et al. Associated Inosine to interferon: results of a clinical trial in multiple sclerosis. Acta Neurol Scand. 2015;131(6):405–10. https://doi.org/10.1111/ane.12333 This study demonstrates the concern raised by multiple authors that high levels of antioxidant therapy, even if an endogenous substance, can have a deleterious effect.

    Article  CAS  PubMed  Google Scholar 

  93. Lovera J, Ramos A, Devier D, Garrison V, Kovner B, Reza T, et al. Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies. J Neurol Sci. 2015;358(1–2):46–52. https://doi.org/10.1016/j.jns.2015.08.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mauriz E, Laliena A, Vallejo D, Tunon MJ, Rodriguez-Lopez JM, Rodriguez-Perez R, et al. Effects of a low-fat diet with antioxidant supplementation on biochemical markers of multiple sclerosis long-term care residents. Nutr Hosp. 2013;28(6):2229–35. https://doi.org/10.3305/nutrhosp.v28in06.6983.

  95. Moretti M, Fraga DB, Rodrigues ALS. Preventive and therapeutic potential of ascorbic acid in neurodegenerative diseases. CNS Neurosci Ther. 2017;23(12):921–9. https://doi.org/10.1111/cns.12767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Maeda T, Guan JZ, Koyanagi M, Makino N. Telomerase activity and telomere length distribution in vascular endothelial cells in a short-term culture under the presence of hydrogen peroxide. Geriatr Gerontol Int. 2013;13(3):774–82. https://doi.org/10.1111/j.1447-0594.2012.00936.x.

    Article  PubMed  Google Scholar 

  97. Pierrot-Deseilligny C, Souberbielle JC. Vitamin D and multiple sclerosis: an update. Mult Scler Relat Disord. 2017;14:35–45. https://doi.org/10.1016/j.msard.2017.03.014.

    Article  PubMed  Google Scholar 

  98. von Geldern G, Mowry EM. The influence of nutritional factors on the prognosis of multiple sclerosis. Nat Rev Neurol. 2012;8(12):678–89. https://doi.org/10.1038/nrneurol.2012.194.

    Article  CAS  Google Scholar 

  99. Spindler M, Beal MF, Henchcliffe C. Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatr Dis Treat. 2009;5:597–610.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Richard D, Kefi K, Barbe U, Bausero P, Visioli F. Polyunsaturated fatty acids as antioxidants. Pharmacol Res. 2008;57(6):451–5. https://doi.org/10.1016/j.phrs.2008.05.002.

    Article  CAS  PubMed  Google Scholar 

  101. Wergeland S, Torkildsen O, Bo L, Myhr KM. Polyunsaturated fatty acids in multiple sclerosis therapy. Acta Neurol Scand Suppl. 2012;195:70–5. https://doi.org/10.1111/ane.12034.

    Article  Google Scholar 

  102. Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z. Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol. 2003;50(4):1129–46.

    CAS  PubMed  Google Scholar 

  103. Emamgholipour S, Hossein-Nezhad A, Sahraian MA, Askarisadr F, Ansari M. Evidence for possible role of melatonin in reducing oxidative stress in multiple sclerosis through its effect on SIRT1 and antioxidant enzymes. Life Sci. 2016;145:34–41. https://doi.org/10.1016/j.lfs.2015.12.014.

    Article  CAS  PubMed  Google Scholar 

  104. Lehmann D, Karussis D, Misrachi-Koll R, Shezen E, Ovadia H, Abramsky O. Oral administration of the oxidant-scavenger N-acetyl-L-cysteine inhibits acute experimental autoimmune encephalomyelitis. J Neuroimmunol. 1994;50(1):35–42.

    Article  CAS  PubMed  Google Scholar 

  105. Touil T, Deloire-Grassin MS, Vital C, Petry KG, Brochet B. In vivo damage of CNS myelin and axons induced by peroxynitrite. Neuroreport. 2001;12(16):3637–44.

    Article  CAS  PubMed  Google Scholar 

  106. Hooper DC, Scott GS, Zborek A, Mikheeva T, Kean RB, Koprowski H, et al. Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood-CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis. FASEB J. 2000;14(5):691–8.

    Article  CAS  PubMed  Google Scholar 

  107. Fraga CG, Galleano M, Verstraeten SV, Oteiza PI. Basic biochemical mechanisms behind the health benefits of polyphenols. Mol Asp Med. 2010;31(6):435–45. https://doi.org/10.1016/j.mam.2010.09.006.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Veterans Affairs Portland Health Care System, Portland, OR, USA

    Carin Waslo MPH & Rebecca Spain MD, MSPH

  2. Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road - L226, Portland, OR, 97239, USA

    Dennis Bourdette MD, Nora Gray PhD, Kirsten Wright ND, MCR, MS & Rebecca Spain MD, MSPH

Authors
  1. Carin Waslo MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dennis Bourdette MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nora Gray PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kirsten Wright ND, MCR, MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rebecca Spain MD, MSPH
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rebecca Spain MD, MSPH.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Multiple Sclerosis and Related Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Waslo, C., Bourdette, D., Gray, N. et al. Lipoic Acid and Other Antioxidants as Therapies for Multiple Sclerosis. Curr Treat Options Neurol 21, 26 (2019). https://doi.org/10.1007/s11940-019-0566-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11940-019-0566-1

Keywords

Search

Navigation