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Lipoic Acid—A Novel Therapeutic Approach for Multiple Sclerosis

Vijayshree Yadav, Gail Marracci, Dennis N Bourdette
US Neurology, 2008;4(2):12-15 DOI: http://doi.org/10.17925/USN.2008.04.02.12
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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that has its symptom onset primarily in young and middle-aged adults. Approximately 400,000 Americans are affected by this chronic and disabling disease, with a significant burden placed on the affected person and his or her family, the healthcare system, and society. MS was described as a clinicopathological entity in the mid-19th century, but significant progress in understanding its pathogenesis has been made only in the past few decades. It is now well established that a dysregulated immune system that targets CNS myelinated tissue including brain, spinal cord, and optic nerves causes MS. Inflammation, focal demyelination, and axonal and neuronal loss are prominent features of the pathology. What triggers the autoimmune response is still not understood. However, our understanding of the pathogenesis of MS has led to the development of treatments that alter the course of the disease.

Until 1993 there were no US Food and Drug Administration (FDA)- approved drugs for MS. Recombinant interferon beta 1b (Betaseron®) became the first disease-modifying treatment available for the illness. Since then, five other FDA-approved drugs have become available for MS treatment. These include two forms of recombinant interferon beta 1a (Avonex®, Rebif®), glatiramer acetate (Copaxone®), mitoxantrone (Novantrone®), and natalizumab (Tysabri®). The interferons and glatiramer acetate work by modulating the immune system and lead to upregulation of the anti-inflammatory response and downregulation of the pro-inflammatory response in MS. Mitoxantrone is a chemotherapy agent that kills the T and B cells and temporarily halts the pro-inflammatory response. Natalizumab, a specific monoclonal antibody to alpha 1 integrin molecule (VLA-4), reduces the ability of activated T cells to cross the blood–brain barrier (BBB). All of these medications reduce disease activity in MS, although none is curative. Despite the availability of these six drugs, there remains a significant need for additional drugs for MS. The use of currently available drugs is limited in that all are available only as injections, are expensive, and can cause significant side effects. Therefore, there is considerable interest in the development of safe oral treatments for MS.

References:
  1. Ziegler D, et al., Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials, Exp Clin Endocrinol Diabetes, 1999;107(7):421–30.
  2. Ziegler D, et al., Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A three-week multicentre randomized controlled trial (ALADIN Study), Diabetologia, 1995;38(12):1425–33.
  3. Ziegler D, et al., Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a seven-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy, Diabetes Care, 1999;22(8):1296–1301.
  4. Ziegler D, Gries F, Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy, Diabetes, 1997;46(Suppl. 2):S62–6.
  5. Marracci GH, et al., 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.
  6. Morini M, et al., Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis, J Neuroimmunol, 2004;148(1–2):146–53.
  7. Biewenga GP, Haenen GR, Bast A, The pharmacology of the antioxidant lipoic acid, Gen Pharmacol, 1997;29(3):315–31.
  8. Hager K, et al., Alpha-lipoic acid as a new treatment option for Alzheimer’s disease—a 48 months follow-up analysis, J Neural Transm Suppl, 2007(72):189–93.
  9. Holmquist L, et al., Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias, Pharmacol Ther, 2007;113(1):154–64.
  10. Prat A, et al., Lymphocyte migration and multiple sclerosis: relation with disease course and therapy, Ann Neurol, 1999;46(2):253–6.
  11. Martino G, Hartung HP, Immunopathogenesis of multiple sclerosis: the role of T cells, Curr Opin Neurol, 1999;12(3):309–21.
  12. Campbell JJ, et al., Chemokines and the arrest of lymphocytes rolling under flow conditions, Science, 1998;279(5349):381–4.
  13. Grabovsky V, et al., Subsecond Induction of α4 Integrin Clustering by Immobilized Chemokines Stimulates Leukocyte Tethering and Rolling on Endothelial Vascular Cell Adhesion Molecule 1 under Flow Conditions, J Exp Med, 2000;192(4):495–506.
  14. Laschinger M, Engelhardt B, Interaction of alpha4-integrin with VCAM-1 is involved in adhesion of encephalitogenic T cell blasts to brain endothelium but not in their transendothelial migration in vitro, J Neuroimmunol, 2000;102(1):32–43.
  15. Pozo MAD, et al., ICAMs Redistributed by Chemokines to Cellular Uropods as a Mechanism for Recruitment of T Lymphocytes, J Cell Biol, 1997;137(2):493–508.
  16. Sellebjerg F, Sorensen TL, Chemokines and matrix metalloproteinase-9 in leukocyte recruitment to the central nervous system, Brain Res Bull, 2003;61(3):347–55.
  17. Cuzner ML, Opdenakker G, Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system, J Neuroimmunol, 1999;94(1–2):1–14.
  18. Hartung HP, Kieseier BC, The role of matrix metalloproteinases in autoimmune damage to the central and peripheral nervous system, J Neuroimmunol, 2000;107(2):140–47.
  19. Leppert D, et al., Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis, Brain Res Brain Res Rev, 2001;36(2–3):249–57.
  20. Liuzzi GM, et al., Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis, Mult Scler, 2002;8(3):222–8.
  21. Madri JA, Graesser D, Cell migration in the immune system: the evolving inter-related roles of adhesion molecules and proteinases, Dev Immunol, 2000;7(2–4):103–16.
  22. Fainardi E, et al., Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis, Mult Scler, 2006;12(3):294–301.
  23. Avolio C, et al., Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes, J Neuroimmunol, 2003;136(1–2):46–53.
  24. Rieckmann P, et al., Correlation of soluble adhesion molecules in blood and cerebrospinal fluid with magnetic resonance imaging activity in patients with multiple sclerosis, Mult Scler, 1998;4(3): 178–82.
  25. Khoury SJ, et al., Changes in serum levels of ICAM and TNF-R correlate with disease activity in multiple sclerosis, Neurology, 1999;53(4):758–64.
  26. Giovannoni G, et al., Serum inflammatory markers and clinical/MRI markers of disease progression in multiple sclerosis, J Neurol, 2001;248(6):487–95.
  27. Elovaara, I., et al., Adhesion molecules in multiple sclerosis: relation to subtypes of disease and methylprednisolone therapy, Arch Neurol, 2000;57(4):546–51.
  28. McDonnell GV, et al., Serum soluble adhesion molecules in multiple sclerosis: raised sVCAM-1, sICAM-1 and sE-selectin in primary progressive disease, J Neurol, 1999;246(2):87–92.
  29. Misu T, Fujihara K, Itoyama Y, Chemokines and chemokine receptors in multiple sclerosis, Nippon Rinsho, 2003;61(8):1422–7.
  30. Hartung HP, et al., Circulating adhesion molecules and inflammatory mediators in demyelination: a review, Neurology, 1995;45(Suppl. 6):S22–32.
  31. Hauser SL, et al., Cytokine accumulations in CSF of multiple sclerosis patients: frequent detection of interleukin-1 and tumor necrosis factor but not interleukin-6, Neurology, 1990;40(11): 1735–9.
  32. Hofman FM, Hinton DR, et al., Tumor necrosis factor identified in multiple sclerosis brain, J Exp Med, 1989;170(2):607–12.
  33. Rudick RA, Ransohoff RN, Cytokine secretion by multiple sclerosis monocytes. Relationship to disease activity, Arch Neurol, 1992;49(3):265–70.
  34. Sharief MK, Hentges R, Thompson EJ, The relationship of interleukin-2 and soluble interleukin-2 receptors to intrathecal immunoglobulin synthesis in patients with multiple sclerosis, J Neuroimmunol, 1991;32(1):43–51.
  35. Trotter JL, Collins KG, van der Veen RC, Serum cytokine levels in chronic progressive multiple sclerosis: interleukin-2 levels parallel tumor necrosis factor-alpha levels, J Neuroimmunol, 1991;33(1): 29–36.
  36. Sharief MK, Hentges R, Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis, N Engl J Med, 1991;325(7):67–72.
  37. Lassmann H, Models of multiple sclerosis: new insights into pathophysiology and repair, Curr Opin Neurol, 2008;21(3):242–7.
  38. Archelos JJ, et al., Inhibition of experimental autoimmune encephalomyelitis by an antibody to the intercellular adhesion molecule ICAM-1, Ann Neurol, 1993;34(2):145–54.
  39. Baron J, et al., Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma, J Exp Med, 1993;177(1):57–68.
  40. Gijbels K, Galardy RE, Steinman L, Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases, J Clin Invest, 1994;94(6):2177–82.
  41. Gordon EJ, et al., Both anti-CD11a (LFA-1) and anti-CD11b (MAC-1) therapy delay the onset and diminish the severity of experimental autoimmune encephalomyelitis, J Neuroimmunol, 1995;62(2):153–60.
  42. Sachse G, Willms B, Efficacy of thioctic acid in the therapy of peripheral diabetic neuropathy, Horm Metab Res Suppl, 1980;9: 105–7.
  43. Yednock TA, et al., Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin, Nature, 1992;356(6364):63–6.
  44. 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.
  45. Marracci GH, et al., Alpha lipoic acid inhibits human T-cell migration: implications for multiple sclerosis, J Neurosci Res, 2004;78(3):362–70.
  46. Schreibelt G, et al., Lipoic acid affects cellular migration into the central nervous system and stabilizes blood–brain barrier integrity, J Immunol, 2006;177(4):2630–37.
  47. Tubridy N, et al., The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group, Neurology, 1999;53(3):466–72.
  48. Linington C, et al., T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system, Eur J Immunol, 1993;23(6):1364–72.
  49. Whitham RH, et al., Lymphocytes from SJL/J mice immunized with spinal cord respond selectively to a peptide of proteolipid protein and transfer relapsing demyelinating experimental autoimmune encephalomyelitis, J Immunol, 1991;146(1):101–7.
  50. Salinthone S, et al., Lipoic acid stimulates cAMP production via the EP2 and EP4 prostanoid receptors and inhibits IFN gamma synthesis and cellular cytotoxicity in NK cells, J Neuroimmunol, 2008;199(1–2):46–55.
  51. Schillace RV, et al., Lipoic acid stimulates cAMP production in T lymphocytes and NK cells, Biochem Biophys Res Commun, 2007;354(1):259–64.
  52. Smith AR, et al., Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress, Curr Med Chem, 2004;11(9):1135–46.
  53. Yadav V, et al., Lipoic acid in multiple sclerosis: a pilot study, Mult Scler, 2005;11(2):159–65.

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