Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients

A randomized clinical trial

Authors

  • Madjid Soltani M.D., Royan Stem Cell Technology, Tehran, Iran

Keywords:

Lipoic acid, Multiple sclerosis, Inflammation, Asymmetric dimethylarginine

Abstract

Background: Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system. Oxidative stress plays a major role in the onset and progression of MS. Asymmetric dimethylarginine (ADMA) formation is dependent on oxidative stress status.

Objective: We examined whether alpha-lipoic acid (ALA) as a potent antioxidant could improve the Expanded Disability Status Scale (EDSS) and decrease plasma level of ADMA in multiple sclerosis patients.

Methods: In a randomized, double-blinded clinical trial conducted at Sina Hospital in Tehran, Iran, from September 2009 to July 2011, 24 patients with relapsing-remitting MS were divided into a treatment group receiving ALA (1200mg/day) for 12 weeks and a control group receiving placebo. Then patients’ EDSS and Plasma levels of ADMA were measured at baseline and 12 weeks later. Statistical analysis was done by SPSS software version 16 using the K-S test, Chi square, Mann–Whitney U-test and Wilcoxon test.

Results: The plasma levels of ADMA in the intervention group were decreased significantly (p=0.04). Also, no patient had increased EDSS score in the supplement group, where 2 out of 12 patients in the placebo group experienced so. Comparing the serum level of ADMA between the two groups failed to show any significant change in the supplement group compared with the control group.

Conclusion: Considering that ADMA is produced by oxidative stress in MS patients and leads to increase of inflammation, ALA may have the potential of beneficial effects in them, in part, by decreasing the plasma level of ADMA and stopping progression.

Trial registration: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: No. IRCT138812222602N2.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

References

Babaloo Z, Babaie F, Farhoodi M, Aliparasti MR, Baradaran B, Almasi S, et al. Interleukin-17A and

Interleukin-17F mRNA Expressions in Peripheral Blood Mononuclear Cells of Patients with Multiple

Sclerosis. Iran J Immunol. 2010; 7(4): 202-9. doi: IJIv7i4A1. PMID: 21189442.

Lassmann H, Brück W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for

diagnosis and therapy. Trends Mol Med. 2001, 7(3): 115-21. doi: 10.1016/S1471-4914(00)01909-2. PMID:

Sandoo A, Dimitroulas T, Hodson J, Smith JP, Douglas KM, Kitas GD. Cumulative inflammation

associates with asymmetric dimethylarginine in rheumatoid arthritis: a 6 year follow-up study.

Rheumatology (Oxford). 2015; 54(7): 1145-52. doi: 10.1093/rheumatology/keu349. PMID: 25187642.

Ghasemi M, Fatemi A. Pathologic role of glial nitric oxide in adult and pediatric neuroinflammatory

diseases. Neurosci Biobehav Rev. 2014; 45: 168-82. doi: 10.1016/j.neubiorev.2014.06.002. PMID:

Smith KJ, Kapoor R, Felts PA. Demyelination: the role of reactive oxygen and nitrogen species. Brain

Pathol. 1999; 9(1): 69-92. doi: 10.1111/j.1750-3639.1999.tb00212.x. PMID: 9989453.

Bö L, Dawson TM, Wesselingh S, Möurk S, Choi S, Kong PA, et al. Induction of nitric oxide synthase in

demyelinating regions of multiple sclerosis brains. Ann Neurol. 1994; 36(5): 778-86. doi:

1002/ana.410360515. PMID: 7526776.

Bagasra O, Michaels FH, Zheng YM, Bobroski LE, Spitsin SV, Fu ZF, et al. Activation of the inducible

form of nitric oxide synthase in the brains of patients with multiple sclerosis. Proc Natl Acad Sci U S A.

; 92(26): 12041-5. doi: 10.1073/pnas.92.26.12041. PMID: 8618840, PMCID: PMC40292.

Endoh M, Maiese K, Wagner J. Expression of the inducible form of nitric oxide synthase by reactive

astrocytes after transient global ischemia. Brain Res. 1994; 651(1-2): 92-100. doi: 10.1016/0006- 8993(94)90683-1. PMID: 7522935.

Lin RF, Lin TS, Tilton RG, Cross AH. Nitric oxide localized to spinal cords of mice with experimental

allergic encephalomyelitis: an electron paramagnetic resonance study. J Exp Med. 1993; 178(2): 643-8.

doi: 10.1084/jem.178.2.643. PMID: 8393479, PMCID: PMC2191106.

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. doi: 10.1007/s00415- 004-0348-9. PMID: 15015004.

Luo Y, Yue W, Quan X, Wang Y, Zhao B, Lu Z. Asymmetric dimethylarginine exacerbates Aβ-induced

toxicity and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease. Free

Radic Biol Med. 2015; 79: 117-26. doi: 10.1016/j.freeradbiomed.2014.12.002. PMID: 25499850.

Moini H, Packer L, Saris NE. Antioxidant and prooxidant activities of α-lipoic acid and dihydrolipoic acid.

Toxicol Appl Pharmacol. 2002; 182(1): 84-90. doi:10.1006/taap.2002.9437. PMID: 12127266.

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. doi: 10.1179/1476830513Y.0000000060. PMID: 23485514.

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. doi: 10.1191/1352458505ms1143oa. PMID:

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. doi: 10.2174/187153008784534303. PMID: 18537699.

Chang JW, Lee EK, Kim TH, Min WK, Chun S, Lee KU, et al. Effects of α-lipoic acid on the plasma levels

of asymmetric dimethylarginine in diabetic end-stage renal disease patients on hemodialysis: a pilot study.

Am J Nephrol. 2007; 27(1): 70-4. doi: 10.1159/000099035. PMID: 17259696.

Mitrovic B, Ignarro LJ, Vinters HV, Akers MA, Schmid I, Uittenbogaart C, et al. Nitric oxide induces

necrotic but not apoptotic cell death in oligodendrocytes. Neuroscience. 1995; 65(2): 531-9. doi:

1016/0306-4522(94)00491-M. PMID: 7777166.

Smith KJ, Lassmann H. The role of nitric oxide in multiple sclerosis. Lancet Neurol. 2002; 1(4): 232-41.

doi: 10.1016/S1474-4422(02)00102-3. PMID: 12849456.

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for

multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69(2): 292-302. doi:

1002/ana.22366. PMID: 21387374, PMCID: PMC3084507.

Pi J, Kumagai Y, Sun G, Shimojo N. Improved method for simultaneous determination of L-arginine and

its mono-and dimethylated metabolites in biological samples by high-performance liquid chromatography.

J Chromatogr B Biomed Sci Appl. 2000; 742(1): 199-203. doi: 10.1016/S0378-4347(00)00145-6. PMID:

Koprowski H, Zheng YM, Heber-Katz E, Fraser N, Rorke L, Fu ZF, et al. In vivo expression of inducible

nitric oxide synthase in experimentally induced neurologic diseases. Proc Natl Acad Sci U S A. 1993;

(7): 3024-7. doi: 10.1073/pnas.90.7.3024. PMID: 7681993, PMCID: PMC46229.

Johnson AW, Land JM, Thompson EJ, Bolaños JP, Clark JB, Heales SJ. Evidence for increased nitric

oxide production in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1995; 58(1): 107. doi:

1136/jnnp.58.1.107. PMID: 7823050, PMCID: PMC1073282.

Stojanovic I, Vojinovic S, Ljubisavljevic S, Pavlovic R, Basic J, Pavlovic D, et al. INF-β1b therapy

modulates l-arginine and nitric oxide metabolism in patients with relapse remittent multiple sclerosis. J

Neurol Sci. 2012; 323(1-2): 187-92. doi: 10.1016/j.jns.2012.09.014. PMID: 23026532.

Conte C, Floridi E, Galli F, Aisa C, Floridi A. A new method for the liquid chromatography analysis of

methylated arginines in biological fluids and tissues by o-phthaldialdehyde postcolumn derivatization. Anal

Biochem. 2005; 338(2): 347-9. doi: 10.1016/j.ab.2004.11.018. PMID: 15745758.

Owczarek D, Cibor D, Mach T. Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine

(SDMA), arginine, and 8‐iso‐prostaglandin F2α (8‐iso‐PGF2α) level in patients with inflammatory

bowel diseases. Inflamm Bowel Dis. 2010; 16(1): 52-7. doi: 10.1002/ibd.20994. PMID: 19575355.

Schreibelt G, Musters RJ, Reijerkerk A, de Groot LR, van der Pol SM, Hendrikx EM, 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. doi: 10.4049/jimmunol.177.4.2630. PMID: 16888025.

Marracci GH, McKeon GP, Marquardt WE, Winter RW, Riscoe MK, Bourdette DN. Alpha lipoic acid

inhibits human T-cell migration: implications for multiple sclerosis. J Neurosci Res. 2004; 78(3): 362-70. doi: 10.1002/jnr.20255. PMID: 15389837.

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. doi: 10.1016/j.jneuroim.2006.03.007. PMID:

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. doi:

1159/000356145. PMID: 24821457.

Mittermayer F, Pleiner J, Francesconi M, Wolzt M. Treatment with α-lipoic acid reduces asymmetric

dimethylarginine in patients with type 2 diabetes mellitus. Transl Res. 2010; 155(1): 6-9. doi:

1016/j.trsl.2009.08.004. PMID: 20004356.

Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine

dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol. 2004; 24(6): 1023-30. doi:

1161/01.ATV.0000128897.54893.26. PMID: 15105281.

Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, et al. Impaired nitric oxide synthase

pathway in diabetes mellitus role of asymmetric dimethylarginine and dimethylarginine

dimethylaminohydrolase. Circulation. 2002; 106(8): 987-92. doi: 10.1161/01.CIR.0000027109.14149.67.

PMID: 12186805.

Leiper J, Vallance P. Biological significance of endogenous methylarginines that inhibit nitric oxide

synthases. Cardiovasc Res. 1999; 43(3): 542-8. doi: 10.1016/S0008-6363(99)00162-5. PMID: 10690326

Published

2022-01-18

Issue

Section

Articles