The Effects of Omega-3 Supplementation on the Expanded Disability Status Scale and Inflammatory Cytokines in Multiple Sclerosis Patients: A Systematic Review and Meta-Analysis

Author(s): Mohsen Sedighiyan, Kurosh Djafarian, Sasan Dabiri, Mina Abdolahi, Sakineh Shab-Bidar*.

Journal Name: CNS & Neurological Disorders - Drug Targets
(Formerly Current Drug Targets - CNS & Neurological Disorders)

Volume 18 , Issue 7 , 2019

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Abstract:

Recent trial studies have shown that omega-3 supplementation can beneficially improve scores on the Expanded Disability Status Scale (EDSS), which is considered a gold standard for measuring disability and disease severity in Multiple Sclerosis (MS) patients, as well as reducing neuroinflammation. The present systematic review and meta-analysis aimed to evaluate the effect of omega-3 supplementation on EDSS and cytokines in MS. A systematic search was performed on Pubmed, Scopus and Cochrane Library up to October 2018. Studies were reviewed based on the Cochrane handbook, and the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Weighted Mean Difference (WMD) with 95% Confidence Intervals (CI) were pooled using a random effects model in order to compare the effects of omega-3 with placebos. Among 4 trials, omega-3 supplementation had no significant effect on EDSS scale (WMD: -0.07; 95% CI: -0.27 to 0.13; P=0.50), as well as serum levels of IL-1β (WMD: -7.67; 95% CI: -23.31 to 7.97; P=0.34) and IL-6 (WMD: -153.57; 95% CI: -455.36 to 148.23; P=0.32). However, omega-3 significantly reduced TNF-α concentration (WMD: -16.76; 95% CI: -18.63 to -14.88; P < 0.00001) compared to placebo. Overall, omega-3 supplementation may not have a clinically considerable impact on EDSS or proinflammatory markers. However, the existing trials are limited in this context, and further clinical trials are required to confirm the potential effects of the omega-3 supplement on MS disease management.

Keywords: Omega-3, EDSS, inflammation, cytokine, meta-analysis, neurogenic disorders.

[1]
Yadav SK, Mindur JE, Ito K, Dhib-Jalbut S. Advances in the immunopathogenesis of multiple sclerosis. Curr Opin Neurol 2015; 28(3): 206-19.
[http://dx.doi.org/10.1097/WCO.0000000000000205] [PMID: 25887768]
[2]
Bărcuţean LI, Romaniuc A, Maier S, et al. Clinical and serological biomarkers of treatment’s response in multiple sclerosis patients treated continuously with interferonβ-1b for more than a decade. CNS Neurol Disord Drug Targets 2018; 17(10): 780-92.
[PMID: 30221605] [http://dx.doi.org/10.2174/1871527317666180917095256]
[3]
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An Expanded Disability Status Scale (EDSS). Neurology 1983; 33(11): 1444-52.
[http://dx.doi.org/10.1212/WNL.33.11.1444] [PMID: 6685237]
[4]
Skjerbæk AG, Boesen F, Petersen T, et al. Can we trust self-reported walking distance when determining EDSS scores in patients with multiple sclerosis? The Danish MS hospitals rehabilitation study. Mult Scler 2018; 25(12): 1653-60.
[http://dx.doi.org/10.1177/1352458518795416] [PMID: 30124106]
[5]
Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: A geographically based study. 2. Predictive value of the early clinical course. Brain 1989; 112(Pt 6): 1419-28.
[http://dx.doi.org/10.1093/brain/112.6.1419] [PMID: 2597989]
[6]
Abdolahi M, Jafarieh A, Sarraf P, et al. The neuromodulatory effects of ω-3 fatty acids and nano-curcumin on the COX-2/iNOS network in migraines: A clinical trial study from gene expression to clinical symptoms. Endocr Metab Immune Disord Drug Targets 2019; 19(6): 874-84.
[http://dx.doi.org/10.2174/1871530319666190212170140] [PMID: 30760195]
[7]
Reza Dorosty-Motlagh A, Mohammadzadeh Honarvar N, Sedighiyan M, Abdolahi M. The molecular mechanisms of vitamin A deficiency in multiple sclerosis. J Mol Neurosci 2016; 60(1): 82-90.
[http://dx.doi.org/10.1007/s12031-016-0781-0] [PMID: 27356515]
[8]
Sadeghian-Rizi T, Behdani M, Khanahmad H, Sadeghi HM, Jahanian-Najafabadi A. Generation and characterization of a functional nanobody against inflammatory chemokine CXCL10, as a novel strategy for treatment of multiple sclerosis. CNS Neurol Disord Drug Targets 2019; 18(2): 141-8.
[http://dx.doi.org/10.2174/1871527317666181114134518] [PMID: 30426906]
[9]
Yaribeygi H, Panahi Y, Javadi B, Sahebkar A. The underlying role of oxidative stress in neurodegeneration: A mechanistic review. CNS Neurol Disord Drug Targets 2018; 17(3): 207-15.
[http://dx.doi.org/10.2174/1871527317666180425122557]
[10]
Boppana S, Huang H, Ito K, Dhib-Jalbut S. Immunologic aspects of multiple sclerosis. Mt Sinai J Med 2011; 78(2): 207-20.
[http://dx.doi.org/10.1002/msj.20249] [PMID: 21425265]
[11]
Ebrahimimonfared M, Ganji A, Zahedi S, Nourbakhsh P, Ghasami K, Mosayebi G. Characterization of regulatory T-cells in multiple sclerosis patients treated with interferon beta-1a. CNS Neurol Disord Drug Targets 2018; 17(2): 113-8.
[http://dx.doi.org/10.2174/1871527317666180327122435] [PMID: 29589548]
[12]
Chen W, Tong W, Guo Y, et al. Upregulation of connexin-43 is critical for irradiation-induced neuroinflammation. CNS Neurol Disord Drug Targets 2018; 17(7): 539-46.
[http://dx.doi.org/10.2174/1871527317666180706124602] [PMID: 29984671]
[13]
Buc M. Role of regulatory T cells in pathogenesis and biological therapy of multiple sclerosis. Mediators Inflamm 2013; 11e963748
[http://dx.doi.org/10.1155/2013/963748]
[14]
Balasa R, Bianca C, Septimiu V, et al. The matrix metalloproteinases panel in multiple sclerosis patients treated with natalizumab: A possible answer to natalizumab non-responders. CNS Neurol Disord Drug Targets 2018; 17(6): 464-72.
[http://dx.doi.org/10.2174/1871527317666180703102536]
[15]
Jadidi-Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol 2011; 74(1): 1-13.
[http://dx.doi.org/10.1111/j.1365-3083.2011.02536.x] [PMID: 21338381]
[16]
Abdolahi M, Yavari P, Honarvar NM, Bitarafan S, Mahmoudi M, Saboor-Yaraghi AA. Molecular mechanisms of the action of vitamin A in Th17/Treg axis in multiple sclerosis. J Mol Neurosci 2015; 57(4): 605-13.
[http://dx.doi.org/10.1007/s12031-015-0643-1] [PMID: 26319266]
[17]
Soveyd N, Abdolahi M, Bitarafan S, et al. Molecular mechanisms of omega-3 fatty acids in the migraine headache. Iran J Neurol 2017; 16(4): 210-7.
[PMID: 29736227]
[18]
Healy-Stoffel M, Levant B. N-3 (omega-3) fatty acids: Effects on brain dopamine systems and potential role in the etiology and treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 2018; 17(3): 216-32.
[http://dx.doi.org/10.2174/1871527317666180412153612] [PMID: 29651972]
[19]
Hong J. NF -κB as a mediator of brain inflammation in Alzheimer’s disease. CNS Neurol Disord Drug Targets 2019; 18(1): 3-10.
[20]
Layé S. Polyunsaturated fatty acids, neuroinflammation and well being. Prostaglandins Leukot Essent Fatty Acids 2010; 82(4-6): 295-303 [PLEFA].
[http://dx.doi.org/10.1016/j.plefa.2010.02.006] [PMID: 20227866]
[21]
He K, Liu K, Daviglus ML, et al. Associations of dietary long-chain N-3 polyunsaturated fatty acids and fish with biomarkers of inflammation and endothelial activation (from the Multi-Ethnic Study of Atherosclerosis [MESA]). Am J Cardiol 2009; 103(9): 1238-43.
[http://dx.doi.org/10.1016/j.amjcard.2009.01.016] [PMID: 19406265]
[22]
Bjørnevik K, Chitnis T, Ascherio A, Munger KL. Polyunsaturated fatty acids and the risk of multiple sclerosis. Mult Scler 2017; 23(14): 1830-8.
[http://dx.doi.org/10.1177/1352458517691150] [PMID: 28156186]
[23]
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med 2009; 151(4): 264-9.
[http://dx.doi.org/10.7326/0003-4819-151-4-200908180-00135] [PMID: 19622511]
[24]
Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions. Wiley-Blackwell Hoboken 2006; pp. 1-257.
[http://dx.doi.org/10.1002/9780470712184]
[25]
Higgins JP, Altman DG, Gøtzsche PC, et al. Methods Group. Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928.
[http://dx.doi.org/10.1136/bmj.d5928] [PMID: 22008217]
[26]
Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods 2010; 1(2): 97-111.
[http://dx.doi.org/10.1002/jrsm.12] [PMID: 26061376]
[27]
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327(7414): 557-60.
[http://dx.doi.org/10.1136/bmj.327.7414.557] [PMID: 12958120]
[28]
Ramirez-Ramirez V, Macias-Islas MA, Ortiz GG, et al. Efficacy of fish oil on serum of TNF α, IL-1 β, and IL-6 oxidative stress markers in multiple sclerosis treated with interferon beta-1b. Oxid Med Cell Longev 2013; 2013709493
[http://dx.doi.org/10.1155/2013/709493] [PMID: 23861993]
[29]
Torkildsen O, Wergeland S, Bakke S, et al. ω-3 fatty acid treatment in multiple sclerosis (OFAMS study): A randomized, double-blind, placebo-controlled trial. Arch Neurol 2012; 69(8): 1044-51.
[http://dx.doi.org/10.1001/archneurol.2012.283] [PMID: 22507886]
[30]
Weinstock-Guttman B, Baier M, Park Y, et al. Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients. Prostaglandins Leukot Essent Fatty Acids 2005; 73(5): 397-404.
[http://dx.doi.org/10.1016/j.plefa.2005.05.024] [PMID: 16099630]
[31]
Zandi-Esfahan S, Fazeli M, Shaygannejad V, et al. Evaluating the effect of adding fish oil to Fingolimod on TNF-α, IL1β, IL6, and IFN-γ in patients with relapsing-remitting multiple sclerosis: A double-blind randomized placebo-controlled trial. Clin Neurol Neurosurg 2017; 163: 173-8.
[http://dx.doi.org/10.1016/j.clineuro.2017.10.004] [PMID: 29126030]
[32]
Skjerbæk AG, Boesen F, Petersen T. Can we trust self-reported walking distance when determining EDSS scores in patients with multiple sclerosis? The Danish MS hospitals rehabilitation study. Mult Scler 2019; 25(12): 1653-60.
[http://dx.doi.org/10.1177/1352458518795416] [PMID: 30124106]
[33]
Rangel-Huerta OD, Aguilera CM, Mesa MD, Gil A. Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: A systematic review of randomised clinical trials. Br J Nutr 2012; 107(Suppl. 2): S159-70.
[http://dx.doi.org/10.1017/S0007114512001559] [PMID: 22591890]
[34]
Calder PC. Omega-3 fatty acids and inflammatory processes: From molecules to man. Biochem Soc Trans 2017; 45(5): 1105-15.
[http://dx.doi.org/10.1042/BST20160474] [PMID: 28900017]
[35]
Kang JX, Weylandt KH. Modulation of inflammatory cytokines by omega-3 fatty acids. Subcell Biochem 2008; 49: 133-43.
[http://dx.doi.org/10.1007/978-1-4020-8831-5_5] [PMID: 18751910] [PMID: 29299991]
[36]
del Campo CP, Tunez I. Crosstalk between gut microbiota and the central nervous system in multiple sclerosis: Strengths, weaknesses, opportunities and threats analysis of the use of an experimental model. CNS Neurol Disord Drug Targets 2017; 16(9): 971-3.
[http://dx.doi.org/ 10.2174/1871527317666180104110111] [PMID: 29299991]
[37]
Solà-Valls N, Vicente-Pascual M, Blanco Y, et al. Spanish validation of the telephone assessed expanded disability status scale and patient determined disease steps in people with multiple sclerosis. Mult Scler Relat Disord 2019; 27: 333-9.
[http://dx.doi.org/10.1016/j.msard.2018.11.018] [PMID: 30472411]
[38]
Millar JH, Zilkha KJ, Langman MJ, et al. Double-blind trial of linoleate supplementation of the diet in multiple sclerosis. BMJ 1973; 1(5856): 765-8.
[http://dx.doi.org/10.1136/bmj.1.5856.765] [PMID: 4571680]
[39]
Bates D, Fawcett PR, Shaw DA, Weightman D. Polyunsaturated fatty acids in treatment of acute remitting multiple sclerosis. BMJ 1978; 2(6149): 1390-1.
[http://dx.doi.org/10.1136/bmj.2.6149.1390] [PMID: 363236]
[40]
Karaca Y, Zhang Y-D, Cattani C, Ayan U. The differential diagnosis of multiple sclerosis using convex combination of infinite kernels. CNS Neurol Disord Drug Targets 2017; 16(1): 36-43.
[http://dx.doi.org/10.2174/1871527315666161024142439]
[41]
Paty DW, Cousin HK, Read S, Adlakha K. Linoleic acid in multiple sclerosis: Failure to show any therapeutic benefit. Acta Neurol Scand 1978; 58(1): 53-8.
[http://dx.doi.org/10.1111/j.1600-0404.1978.tb02859.x] [PMID: 707035]
[42]
Kumar A, Datusalia AK. Metabolic stress and inflammation: Implication in treatment for neurological disorders. CNS Neurol Disord Drug Targets 2018; 17(9): 642-3.
[43]
Soveyd N, Abdolahi M, Djalali M, et al. The combined effects of ω-3 fatty acids and nano-curcumin supplementation on intercellular adhesion molecule-1 (ICAM-1) gene expression and serum levels in migraine patients. CNS Neurol Disord Drug Targets 2017; 16(10): 1120-6.
[44]
Zhao Y, Calon F, Julien C, et al. Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPARγ-mediated mechanisms in Alzheimer’s disease models. PLoS One 2011; 6(1)e15816
[http://dx.doi.org/10.1371/journal.pone.0015816] [PMID: 21246057]
[45]
Ortiz GG, Pacheco-Moisés FP, Gómez-Rodríguez VM, González-Renovato ED, Torres-Sánchez ED, Ramírez-Anguiano AC. Fish oil, melatonin and vitamin E attenuates midbrain cyclooxygenase-2 activity and oxidative stress after the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Metab Brain Dis 2013; 28(4): 705-9.
[http://dx.doi.org/10.1007/s11011-013-9416-0] [PMID: 23703110]
[46]
Abdolahi M, Sarraf P, Javanbakht MH, et al. A novel combination of ω-3 fatty acids and nano-curcumin modulates interleukin-6 gene expression and high sensitivity c-reactive protein serum levels in patients with migraine: A randomized clinical trial study. CNS Neurol Disord Drug Targets 2018; 17(6): 430-8.
[http://dx.doi.org/ 10.2174/1871527317666180625101643] [PMID: 29938621]
[47]
Abdolahi M, Tafakhori A, Togha M, et al. The synergistic effects of ω-3 fatty acids and nano-curcumin supplementation on Tumor Necrosis Factor (TNF)-α gene expression and serum level in migraine patients. Immunogenetics 2017; 69(6): 371-8.
[http://dx.doi.org/10.1007/s00251-017-0992-8] [PMID: 28478481]
[48]
Sadeghian-Rizi T, Khanahmad H, Jahanian-Najafabadi A. Therapeutic targeting of chemokines and chemokine receptors in multiple sclerosis: Opportunities and challenges. CNS Neurol Disord Drug Targets 2018; 17(7): 496-508.
[http://dx.doi.org/10.2174/1871527317666180713111100]
[49]
Arshad N, Lin TS, Yahaya MF. Metabolic syndrome and its effect on the brain: Possible mechanism. CNS Neurol Disord Drug Targets 2018; 17(8): 595-603.
[http://dx.doi.org/10.2174/1871527317666180724143258]
[50]
Nüesch E, Trelle S, Reichenbach S, et al. Small study effects in meta-analyses of osteoarthritis trials: Meta-epidemiological study. BMJ 2010; 341: c3515.
[http://dx.doi.org/10.1136/bmj.c3515] [PMID: 20639294]
[51]
Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: Power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000; 53(11): 1119-29.
[http://dx.doi.org/10.1016/S0895-4356(00)00242-0] [PMID: 11106885]
[52]
Shinto L, Marracci G, Mohr DC, et al. Omega-3 fatty acids for depression in multiple sclerosis: A randomized pilot study. PLoS One 2016; 11(1)e0147195
[http://dx.doi.org/10.1371/journal.pone.0147195]
[53]
Torres-Sánchez ED, Pacheco-Moisés FP, Macias-Islas MA, et al. Effect of fish and olive oil on mitochondrial ATPase activity and membrane fluidity in patients with relapsing-remitting multiple sclerosis treated with interferon beta 1-b. Nutr Hosp 2018; 35(1): 162-8.
[PMID: 29565165]


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VOLUME: 18
ISSUE: 7
Year: 2019
Page: [523 - 529]
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DOI: 10.2174/1871527318666190516083008
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