Molecular mechanisms of omega-3 fatty acids in the migraine headache

  • Neda Soveyd Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
  • Mina Abdolahi Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
  • Sama Bitarafan Iranian Centre of Neurological Research, Neuroscience institute, Department of Neurology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
  • Abbas Tafakhori Iranian Centre of Neurological Research, Neuroscience institute, Department of Neurology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
  • Payam Sarraf Iranian Centre of Neurological Research, Neuroscience institute, Department of Neurology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
  • Mansoureh Togha Headache Department, Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
  • Ali Asghar Okhovat Headache Department, Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
  • Mahsa Hatami Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
  • Mohsen Sedighiyan Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
  • Mahmoud Djalali Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
  • Niyaz Mohammadzadeh-Honarvar Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
Keywords: Omega 3 Fatty Acids, Migraine, Neuroinflammation, Headache


Migraine is a common chronic inflammatory neurological disease with the progressive and episodic course. Much evidence have shown a role of inflammation in the pathogenesis of migraine. Omega-3 fatty acids are an important components of cell membranes phospholipids. The intake of these fatty acids is related to decrease concentration of C-reactive protein (CRP), proinflammatory eicosanoids, cytokines, chemokines and other inflammation biomarkers. Many of clinical trials have shown the beneficial effect of dietary supplementation with omega-3 fatty acids in inflammatory and autoimmune diseases in human, including Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), multiple sclerosis (MS) and migraine headaches. Therefore, omega-3 fatty acids as an alternative therapy can be potentially important. This review focuses on the pathogenesis of a migraine, with an emphasis on the role of omega-3 fatty acid and its molecular mechanisms.


1. Robbins MS, Ailani J. Epidemiology, progression, prognosis, and comorbidity of trigeminal autonomic cephalalgias. In: Robbins M, Grosberg BM, Lipton R, Editors. Headache. New York, NY: John Wiley & Sons; 2013. p. 192-200.
2. Hamed SA. The vascular risk associations with migraine: Relation to migraine susceptibility and progression. Atherosclerosis 2009; 205(1): 15-22.
3. Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and severe headache in the United States: Updated statistics from government health surveillance studies. Headache 2015; 55(1): 21-34.
4. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: Data from the American Migraine Study II. Headache 2001; 41(7): 646-57.
5. Goua M, Mulgrew S, Frank J, Rees D,Sneddon AA, Wahle KW. Regulation of adhesion molecule expression in human endothelial and smooth muscle cells by omega-3 fatty acids and conjugated linoleic acids: Involvement of the transcription factor NF-kappaB? Prostaglandins Leukot Essent Fatty Acids2008; 78(1): 33-43.
6. Rodriguez-Osorio X, Sobrino T, Brea D, Martinez F, Castillo J, Leira R. Endothelial progenitor cells: A new key for endothelial dysfunction in migraine.Neurology 2012; 79(5): 474-9.
7. DosSantos MF, Holanda-Afonso RC, Lima RL, DaSilva AF, Moura-Neto V. The role of the blood-brain barrier in the development and treatment of migraine and other pain disorders. Front Cell Neurosci 2014; 8: 302.
8. Forman MS, Lal D, Zhang B, Dabir DV, Swanson E, Lee VM, et al. Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. J Neurosci 2005; 25(14):3539-50.
9. De Caterina R, Madonna R, Massaro M.Effects of omega-3 fatty acids on cytokines and adhesion molecules. Curr Atheroscler Rep 2004; 6(6): 485-91.
10. Sedighiyan M, Abdolahi M, Mohammadzadeh Honarvar N, Hosseini B, Djafarian K. Curcumin a novel agent targeting inflammatory pathways in obesity. Journal of Nutritional Sciencesand Dietetics 2016; 2(5).
11. Calder PC. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 2006; 83(6
Suppl): 1505S-19S.
12. Abdolahi M, Tafakhori A, Togha M, Okhovat AA, Siassi F, Eshraghian MR, et al. The synergistic effects of omega-3 fatty acids and nano-curcumin supplementation on tumor necrosis factor (TNF)-alpha gene expression and serum level in migraine patients. Immunogenetics 2017; 69(6): 371-8.
13. Streit WJ. Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 2002; 40(2): 133-9.
14. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell 2010; 140(6): 918-34.
15. Libby P. Inflammatory mechanisms: The molecular basis of inflammation and disease. Nutr Rev 2007; 65(12 Pt 2): S140-S146.
16. Streit WJ, Mrak RE, Griffin WS.Microglia and neuroinflammation: A pathological perspective. J Neuroinflammation 2004; 1(1): 14.
17. Akiyama H. Inflammatory response in Alzheimer's disease. Tohoku J Exp Med 1994; 174(3): 295-303.
18. Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of immune system-associated antigens by cells of the human central nervous system: Relationship to the pathology of Alzheimer's disease. Neurobiol Aging 1988; 9(4): 339-49.
19. Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: Mechanisms and strategies for therapeutic
intervention. J Pharmacol Exp Ther 2003;304(1): 1-7.
20. Mohammadzadeh Honarvar N, Saedisomeolia A, Abdolahi M, Shayeganrad A, Taheri Sangsari G,Hassanzadeh RB, et al. Molecular anti-
inflammatory mechanisms of retinoids and carotenoids in Alzheimer's disease: A review of current evidence. J Mol Neurosci 2017; 61(3): 289-304.
21. Maragakis NJ, Rothstein JD. Mechanisms of Disease: Astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2006; 2(12): 679-89.
22. Danbolt NC. Glutamate uptake. Prog Neurobiol 2001; 65(1): 1-105.
23. Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 1997; 276(5319): 1699-702.
24. Nutt JG, Wooten GF. Clinical practice.Diagnosis and initial management ofParkinson's disease. N Engl J Med 2005;353(10): 1021-7.
25. Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 2003; 302(5642):113-7.
26. Floyd RA. Neuroinflammatory processes are important in neurodegenerative diseases: An hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development. Free Radic Biol Med 1999;26(9-10): 1346-55.
27. Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 2002; 21(6): 495-505.
28. Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 2009;457(7232): 981-9.
29. McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: Implications for normal brain function and neurodegenerative disease. JNeuroinflammation 2008; 5: 45.
30. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 2009; 137(1): 47-59.
31. Sastre M, Walter J, Gentleman SM.Interactions between APP secretases and inflamatory mediators. J Neuroinflammation 2008; 5: 25.
32. Rissman RA, De Blas AL, Armstrong DM. GABA(A) receptors in aging and Alzheimer's disease. J Neurochem 2007;103(4): 1285-92.
33. Zipp F, Aktas O. The brain as a target of inflammation: Common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci 2006; 29(9): 518-27.
34. Reza Dorosty-Motlagh A, Mohammadzadeh HN, Sedighiyan M, Abdolahi M. The molecular mechanisms of vitamin a deficiency in multiplesclerosis. J Mol Neurosci 2016;60(1):82-90.
35. Mohammadzadeh Honarvar N, Harirchian MH, Abdolahi M, Abedi E, Bitarafan S, Koohdani F, et al. Retinyl palmitate supplementation modulates tbet and interferon gamma gene expression in multiple sclerosis patients. J Mol Neurosci 2016; 59(3): 360-5.
36. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421(6924): 744-8.
37. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol 2009; 27: 485-517.
38. 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.
39. Hirsch EC, Hunot S. Neuroinflammation in Parkinson's disease: A target for neuroprotection? Lancet Neurol 2009;8(4): 382-97.
40. Davie CA. A review of Parkinson's disease. Br Med Bull 2008; 86: 109-27.
41. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003; 24(2): 197-211.
42. Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F. Glutathione peroxidase, glial cells and Parkinson's disease.
Neuroscience 1993; 52(1): 1-6.
43. Reynolds AD, Kadiu I, Garg SK, Glanzer JG, Nordgren T, Ciborowski P, et al. Nitrated alpha-synuclein and microglial neuroregulatory activities. J Neuroimmune Pharmacol 2008; 3(2): 59-74.
44. Roodveldt C, Christodoulou J, Dobson CM. Immunological features of alpha- synuclein in Parkinson's disease. J Cell Mol Med 2008; 12(5B): 1820-9.
45. Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, et al. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 2008;3(1): e1376.
46. McGeer PL, McGeer EG. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 2002; 26(4): 459-70.
47. Turner BJ, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol 2008; 85(1): 94-134.
48. Amit I, Garber M, Chevrier N, Leite AP, Donner Y, Eisenhaure T, et al. Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses. Science 2009;326(5950): 257-63.
49. Longoni M, Ferrarese C. Inflammation and excitotoxicity: Rrole in migraine pathogenesis. Neurol Sci 2006; 27(Suppl 2): S107-S110.
50. D'Andrea G, Leon A. Pathogenesis of migraine: From neurotransmitters to neuromodulators and beyond. Neurol Sci 2010; 31(Suppl 1): S1-S7.
51. Abdolahi M, Mohammadzadeh Honarvar N, Tafakhori A, Sarraf P, Hatami M, Soveyd N, et al. The combined effects of omega3 fatty acids and nanocurcumin supplementation on gene expression and serum levels of some inflammatory and endothelial factors in migraine patients: Study protocol for a randomized controlled trial. Int J Pharm Sci Invent 2016; 5(3): 42-6.
52. Kors EE, Vanmolkot KR, Haan J, Frants RR, van den Maagdenberg AM, Ferrari MD. Recent findings in headache genetics. Curr Opin Neurol 2004; 17(3):283-8.
53. Olsen TS. Pathophysiology of the migraine aura: The spreading depression theory. Brain 1995; 118 (Pt 1): 307-8.
54. Pietrobon D. Migraine: New molecular mechanisms. Neuroscientist 2005; 11(4):373-86.
55. Hargreaves RJ, Shepheard SL.Pathophysiology of migraine-new insights. Can J Neurol Sci 1999; 26(Suppl 3): S12-S19.
56. Gallai V, Sarchielli P, Coata G, Firenze C, Morucci P, Abbritti G. Serum and salivary magnesium levels in migraine. Results in a group of juvenile patients. Headache 1992; 32(3): 132-5.
57. Ramadan NM, Halvorson H, Vande-Linde A, Levine SR, Helpern JA, Welch KM. Low brain magnesium in migraine. Headache 1989; 29(9): 590-3.
58. Huang QF, Gebrewold A, Zhang A, Altura BT, Altura BM. Role of excitatory amino acids in regulation of rat pial microvasculature. Am J Physiol 1994;266(1 Pt 2): R158-R163.
59. Sun-Edelstein C, Mauskop A. Role of magnesium in the pathogenesis and treatment of migraine. Expert Rev Neurother 2009; 9(3): 369-79.
60. Coan EJ, Collingridge GL. Magnesium ions block an N-methyl-d-aspartate receptor-mediated component of synaptic transmission in rat hippocampus. Neurosci Lett 1985; 53(1): 21-6.
61. Lance JW, Goadsby PJ. Mechanism and Management of Headache. 7th ed. Philadelphia, PA: Elsevier, Butterworth, Heinemann; 2005.
62. Peroutka SJ. Dopamine and migraine.Neurology 1997; 49(3): 650-6.
63. Coppola G, Pierelli F, Schoenen J.Habituation and migraine. Neurobiol Learn Mem 2009; 92(2): 249-59.
64. Durham P, Papapetropoulos S.Biomarkers associated with migraine and their potential role in migraine management. Headache 2013; 53(8):1262-77.
65. Saegusa H, Tanabe T. N-type voltage- dependent Ca2+ channel in non-excitable microglial cells in mice is involved in the pathophysiology of neuropathic pain. Biochem Biophys Res Commun 2014;450(1): 142-7.
66. Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: The anti- inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev 2010;68(5): 280-9.
67. Xu ZZ, Zhang L, Liu T, Park JY, Berta T, Yang R, et al. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nat Med 2010;16(5): 592-7, 1p.
68. Bazan NG, Molina MF, Gordon WC.Docosahexaenoic acid signalolipidomics in nutrition: Significance in aging, neuroinflammation, macular degeneration, Alzheimer's, and other neurodegenerative diseases. Annu Rev Nutr 2011; 31: 321-51.
69. Corsi L, Dongmo BM, Avallone R.Supplementation of omega 3 fatty acids improves oxidative stress in activated BV2 microglial cell line. Int J Food Sci Nutr 2015; 66(3): 293-9.
70. Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The national institute on aging,and Reagan institute working group on diagnostic criteria for the neuropathological assessment of Alzheimer's disease. Neurobiol Aging
1997; 18(4 Suppl): S1-S2.
71. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al. The consortium to establish a registry for alzheimer's disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991; 41(4): 479-86.
72. Lukiw WJ, Bazan NG. Docosahexaenoic acid and the aging brain. J Nutr 2008;138(12): 2510-4.
73. Bazan NG. Neuroprotectin D1 (NPD1): A DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. Brain Pathol 2005;15(2): 159-66.
74. Montine TJ, Morrow JD. Fatty acid oxidation in the pathogenesis of Alzheimer's disease. Am J Pathol 2005;166(5): 1283-9.
75. Farooqui AA, HorrocksA.Phospholipase A2-generated lipid mediators in the brain: The good, the bad, and the ugly. Neuroscientist 2006; 12(3):245-60.
76. Calder PC. Dietary modification of inflammation with lipids. Proc Nutr Soc 2002; 61(3): 345-58.
77. Voigt RG, Llorente AM, Jensen CL, Fraley JK, Berretta MC, Heird WC. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr 2001; 139(2): 189-96.
78. Peet M. Nutrition and schizophrenia: Beyond omega-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids2004; 70(4): 417-22.
79. Peet M. Eicosapentaenoic acid in thetreatment of schizophrenia and depression: Rationale and preliminary double-blind clinical trial results. Prostaglandins Leukot Essent Fatty Acids2003; 69(6): 477-85.
80. Vancassel S, Durand G, Barthelemy C, Lejeune B, Martineau J, Guilloteau D, et al. Plasma fatty acid levels in autistic children. Prostaglandins Leukot Essent Fatty Acids 2001; 65(1): 1-7.
81. Kris-Etherton PM, Taylor DS, Yu-Poth S,Huth P, Moriarty K, Fishell V, et al.Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr 2000; 71(1 Suppl): 179S-88S.
82. Dyall SC, Michael-Titus AT.Neurological benefits of omega-3 fatty acids. euromolecular Med 2008; 10(4):
219-35. 83. Laye S. Polyunsaturated fatty acids, neuroinflammation and ell-ing. Prostaglandins Leukot ssent atty Acids2010; 82(4-6): 295-303.
84. Tajmirriahi M, Sohelipour M, Basiri K,Shaygannejad V, Ghorbani A, Saadatnia M. The effects of sodium valproate with fish oil supplementation or alone in migraine prevention: A randomized single-blind clinical trial. Iran J Neurol 2012; 11(1): 21-4.
85. Harel Z, Gascon G, Riggs S, Vaz R, Brown W, Exil G. Supplementation with omega-3 polyunsaturated fatty acids in the management of recurrent migraines in adolescents. J Adolesc Health 2002;31(2): 154-61.
How to Cite
Soveyd N, Abdolahi M, Bitarafan S, Tafakhori A, Sarraf P, Togha M, Okhovat AA, Hatami M, Sedighiyan M, Djalali M, Mohammadzadeh-Honarvar N. Molecular mechanisms of omega-3 fatty acids in the migraine headache. IJNL. 16(4):210-7.
Review Article(s)