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Endocrine, Metabolic & Immune Disorders - Drug Targets


ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Clinical Trial

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

Author(s): Mina Abdolahi, Arash Jafarieh, Payam Sarraf, Mohsen Sedighiyan, Abolghasem Yousefi, Abbas Tafakhori, Hamed Abdollahi, Farahnaz Salehinia and Mahmoud Djalali*

Volume 19, Issue 6, 2019

Page: [874 - 884] Pages: 11

DOI: 10.2174/1871530319666190212170140

Price: $65


Background: Migraine is a common neuroinflammatory disorder characterized by recurrent attacks of pain. Human and experimental models of migraine studies have demonstrated the role played by COX-2/ iNOS in migraine’s neuroinflammatory pathogenesis. COX-2 and iNOS are closely linked and both contribute to inflammation and neurogenic pain in the central nervous system. Omega- 3 fatty acids and curcumin, an active polyphenol of turmeric, have anti-inflammatory and neuroprotective effects through several mechanisms, including the suppression of COX-2 and iNOS gene expression, as well as their serum levels. The aim of the present study is to evaluate the nutrigenomic effects of ω-3 fatty acids, nano-curcumin, and a combination of the two, on neuroinflammation and clinical symptoms in migraine patients.

Methods: This study reports the results of a clinical trial over a 2-month period, involving 74 episodic migraine patients who received ω-3 fatty acids, nano-curcumin, a combination of them, or a placebo. At the start and end of the study, the expression of COX-2/iNOS (in peripheral mononuclear blood cells isolated from patients) and COX-2/iNOS serum levels were measured, using real-time PCR and ELISA respectively. The frequency, severity and duration of pain attacks were also recorded.

Results: The results of the present trial showed that ω-3 fatty acids and nano-curcumin can reinforce each other’s effects in the downregulation of COX-2/iNOS mRNA, as well as reduce their serum levels. In addition, the combination of ω-3 and nano-curcumin significantly reduced the frequency, severity and duration of headaches (P<0.05).

Conclusion: These findings indicate that combination therapy of ω-3 fatty acids and nano-curcumin can be considered as a promising new approach in migraine prevention.

Keywords: Migraine, curcumin, ω-3 fatty acids, COX-2, iNOS, headache.

Graphical Abstract
Smitherman, T.A.; Burch, R.; Sheikh, H.; Loder, E. The prevalence, impact, and treatment of migraine and severe headaches in the United States: a review of statistics from national surveillance studies. Headache, 2013, 53(3), 427-436.
[] [PMID: 23470015]
Zameel Cader, M. The molecular pathogenesis of migraine: new developments and opportunities. Hum. Mol. Genet., 2013, 22(R1), R39-R44.
[] [PMID: 23922230]
Malhotra, R. Understanding migraine: Potential role of neurogenic inflammation. Ann. Indian Acad. Neurol., 2016, 19(2), 175-182.
[] [PMID: 27293326]
Liddle, R.A.; Nathan, J.D. Neurogenic inflammation and pancreatitis. Pancreatology, 2004, 4(6), 551-559.
[] [PMID: 15550764]
Barbanti, P.; Egeo, G.; Aurilia, C.; Fofi, L.; Della-Morte, D. Drugs targeting nitric oxide synthase for migraine treatment. Expert Opin. Investig. Drugs, 2014, 23(8), 1141-1148.
[] [PMID: 24818644]
Ramachandran, R.; Bhatt, D.K.; Ploug, K.B.; Hay-Schmidt, A.; Jansen-Olesen, I.; Gupta, S.; Olesen, J. Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation. Cephalalgia, 2014, 34(2), 136-147.
[] [PMID: 24000375]
Kawabata, A. Prostaglandin E2 and pain--an update. Biol. Pharm. Bull., 2011, 34(8), 1170-1173.
[] [PMID: 21804201]
Tassorelli, C.; Greco, R.; Armentero, M.T.; Blandini, F.; Sandrini, G.; Nappi, G. A role for brain cyclooxygenase-2 and prostaglandin-E2 in migraine: effects of nitroglycerin. Int. Rev. Neurobiol., 2007, 82, 373-382.
[] [PMID: 17678972]
Stirparo, G.; Zicari, A.; Favilla, M.; Lipari, M.; Martelletti, P. Linked activation of nitric oxide synthase and cyclooxygenase in peripheral monocytes of asymptomatic migraine without aura patients. Cephalalgia, 2000, 20(2), 100-106.
[] [PMID: 10961765]
Varga, H.; Pardutz, A.; Vamos, E.; Plangar, I.; Egyud, E.; Tajti, J.; Bari, F.; Vecsei, L. Cox-2 inhibitor attenuates NO-induced nNOS in rat caudal trigeminal nucleus. Headache, 2007, 47(9), 1319-1325.
[] [PMID: 17927648]
Dong, X.; Hu, Y.; Jing, L.; Chen, J. Role of phosphorylated extracellular signal-regulated kinase, calcitonin gene-related peptide and cyclooxygenase-2 in experimental rat models of migraine. Mol. Med. Rep., 2015, 12(2), 1803-1809.
[] [PMID: 25892078]
Hoffmann, J.; Goadsby, P.J. New agents for acute treatment of migraine: CGRP receptor antagonists, iNOS inhibitors. Curr. Treat. Options Neurol., 2012, 14(1), 50-59.
[] [PMID: 22090312]
Sedighiyan, M.; Abdolahi, M.; Honarvar, N.M.; Hosseini, B.; Djafarian, K. Curcumin a novel agent targeting inflammatory pathways in obesity. J. Nutr Sci. Diet., 2016, 2(5)
Bazan, N.G.; Molina, M.F.; Gordon, W.C. Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer’s, and other neurodegenerative diseases. Annu. Rev. Nutr., 2011, 31, 321-351.
[] [PMID: 21756134]
Hatami, M.; Abdolahi, M.; Soveyd, N.; Djalali, M.; Togha, M.; Honarvar, N. Molecular Mechanisms of Curcumin in Neuroinflammatory Disorders: A Mini Review of Current Evidences. Endocr. Metab. Immune Disord. Drug Targets, 2018.
[PMID: 30488803]
Jia, Q.; Ivanov, I.; Zlatev, Z.Z.; Alaniz, R.C.; Weeks, B.R.; Callaway, E.S.; Goldsby, J.S.; Davidson, L.A.; Fan, Y-Y.; Zhou, L.; Lupton, J.R.; McMurray, D.N.; Chapkin, R.S. Dietary fish oil and curcumin combine to modulate colonic cytokinetics and gene expression in dextran sodium sulphate-treated mice. Br. J. Nutr., 2011, 106(4), 519-529.
[] [PMID: 21401974]
Layé, S. Polyunsaturated fatty acids, neuroinflammation and well being. Prostaglandins Leukot. Essent. Fatty Acids, 2010, 82(4-6), 295-303.
[] [PMID: 20227866]
Soveyd, N.; Abdolahi, M.; Bitarafan, S.; Tafakhori, A.; Sarraf, P.; Togha, M.; Okhovat, A.A.; Hatami, M.; Sedighiyan, M.; Djalali, M.; Mohammadzadeh Honarvar, N. Molecular mechanisms of omega-3 fatty acids in the migraine headache. Iran. J. Neurol., 2017, 16(4), 210-217.
[PMID: 29736227]
Shehzad, A.; Lee, Y. Curcumin: Multiple molecular targets mediate multiple pharmacological actions: A review. Drugs Future, 2010, 35(2), 113.
Kunnumakkara, A.B.; Bordoloi, D.; Padmavathi, G.; Monisha, J.; Roy, N.K.; Prasad, S.; Aggarwal, B.B. Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br. J. Pharmacol., 2016.
[PMID: 27638428]
Goel, A.; Kunnumakkara, A.B.; Aggarwal, B.B. Curcumin as “Curecumin”: from kitchen to clinic. Biochem. Pharmacol., 2008, 75(4), 787-809.
[] [PMID: 17900536]
Shishodia, S. Molecular mechanisms of curcumin action: gene expression. Biofactors, 2013, 39(1), 37-55.
[] [PMID: 22996381]
Kanai, M.; Imaizumi, A.; Otsuka, Y.; Sasaki, H.; Hashiguchi, M.; Tsujiko, K.; Matsumoto, S.; Ishiguro, H.; Chiba, T. Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. Cancer Chemother. Pharmacol., 2012, 69(1), 65-70.
[] [PMID: 21603867]
Sasaki, H.; Sunagawa, Y.; Takahashi, K.; Imaizumi, A.; Fukuda, H.; Hashimoto, T.; Wada, H.; Katanasaka, Y.; Kakeya, H.; Fujita, M.; Hasegawa, K.; Morimoto, T. Innovative preparation of curcumin for improved oral bioavailability. Biol. Pharm. Bull., 2011, 34(5), 660-665.
[] [PMID: 21532153]
Mittal, N.; Joshi, R.; Hota, D.; Chakrabarti, A. Evaluation of antihyperalgesic effect of curcumin on formalin-induced orofacial pain in rat. Phytother. Res., 2009, 23(4), 507-512.
[] [PMID: 19051211]
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), 21-24.
[PMID: 24250854]
Lei, E.; Vacy, K.; Boon, W.C. Fatty acids and their therapeutic potential in neurological disorders. Neurochem. Int., 2016, 95, 75-84.
[] [PMID: 26939763]
Lipton, R.B.; Stewart, W.F.; Diamond, S.; Diamond, M.L.; Reed, M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache, 2001, 41(7), 646-657.
[] [PMID: 11554952]
Soveyd, N.; Abdolahi, M.; Djalali, M.; Hatami, M.; Tafakhori, A.; Sarraf, P.; Honarvar, N.M. 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, 2018, 16(10), 1120-1126.
[] [PMID: 29237386]
Abdolahi, M.; Sarraf, P.; Javanbakht, M.H.; Honarvar, N.M.; Hatami, M.; Soveyd, N.; Tafakhori, A.; Sedighiyan, M.; Djalali, M.; Jafarieh, A.; Masoudian, Y.; Djalali, M. 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), 430-438.
[] [PMID: 29938621]
Abdolahi, M.; Mohammadzadeh Honarvar, N.; Tafakhori, A.; Sarraf, P.; Hatami, M.; Soveyd, N. 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), 42-46.
Abdolahi, M.; Tafakhori, A.; Togha, M.; Okhovat, A.A.; Siassi, F.; Eshraghian, M.R.; Sedighiyan, M.; Djalali, M.; Mohammadzadeh Honarvar, N.; Djalali, M. 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), 371-378.
[] [PMID: 28478481]
Gerring, Z.F.; Powell, J.E.; Montgomery, G.W.; Nyholt, D.R. Genome-wide analysis of blood gene expression in migraine implicates immune-inflammatory pathways. Cephalalgia, 2017.0333102416686769,
[PMID: 28058943]
Koistinaho, M.; Kettunen, M.I.; Goldsteins, G.; Keinänen, R.; Salminen, A.; Ort, M.; Bures, J.; Liu, D.; Kauppinen, R.A.; Higgins, L.S.; Koistinaho, J. β-amyloid precursor protein transgenic mice that harbor diffuse A β deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. Proc. Natl. Acad. Sci. USA, 2002, 99(3), 1610-1615.
[] [PMID: 11818564]
Hsieh, H.-L.; Yang, C.-M. Role of redox signaling in neuroinflammation and neurodegenerative diseases. BioMed Res. Int 2013, 2013,
Tocco, G.; Freire-Moar, J.; Schreiber, S.S.; Sakhi, S.H.; Aisen, P.S.; Pasinetti, G.M. Maturational regulation and regional induction of cyclooxygenase-2 in rat brain: implications for Alzheimer’s disease. Exp. Neurol., 1997, 144(2), 339-349.
[] [PMID: 9168834]
Wang, H.H.; Hsieh, H.L.; Yang, C.M. Nitric oxide production by endothelin-1 enhances astrocytic migration via the tyrosine nitration of matrix metalloproteinase-9. J. Cell. Physiol., 2011, 226(9), 2244-2256.
[] [PMID: 21660948]
Giacalone, A.; Montalto, G.; Giannitrapani, L.; Balasus, D.; Terranova, A.; Cervello, M.; Soresi, M.; Marasà, L. Association between single nucleotide polymorphisms in the cyclooxygenase-2, tumor necrosis factor-α, and vascular endothelial growth factor-A genes, and susceptibility to hepatocellular carcinoma. OMICS, 2011, 15(3), 193-196.
[] [PMID: 21319995]
Gonçalves, F.M.; Luizon, M.R.; Speciali, J.G.; Martins-Oliveira, A.; Dach, F.; Tanus-Santos, J.E. Interaction among nitric oxide (NO)-related genes in migraine susceptibility. Mol. Cell. Biochem., 2012, 370(1-2), 183-189.
[] [PMID: 22865486]
Zhu, Y.; Zhu, M.; Lance, P. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts. Exp. Cell Res., 2012, 318(16), 2116-2127.
[] [PMID: 22683859]
Franco, L.; Talamini, G. Cross-talk between inducible nitric oxide synthase and cyclooxygenase in Helicobacter-pylori-induced gastritis. Med. Princ. Pract., 2009, 18(6), 477-481.
[] [PMID: 19797925]
Sarchielli, P.; Alberti, A.; Codini, M.; Floridi, A.; Gallai, V. Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia, 2000, 20(10), 907-918.
[] [PMID: 11304026]
Kim, S.F.; Huri, D.A.; Snyder, S.H. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science, 2005, 310(5756), 1966-1970.
[] [PMID: 16373578]
Martelletti, P.; Zicari, A.; Realacci, M.; Fiore, G.; De Filippis, S.; Stirparo, G.; Denora, P.; Solimeo, M.D.; Rinaldi, C.; Morrone, S. Expression of NOS-2, COX-2 and Th1/Th2 cytokines in migraine. J. Headache Pain, 2001, 2(1), s51-s56.
Gupta, S.C.; Patchva, S.; Aggarwal, B.B. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J., 2013, 15(1), 195-218.
[] [PMID: 23143785]
Saw, C.L.L.; Huang, Y.; Kong, A-N. Synergistic anti-inflammatory effects of low doses of curcumin in combination with polyunsaturated fatty acids: docosahexaenoic acid or eicosapentaenoic acid. Biochem. Pharmacol., 2010, 79(3), 421-430.
[] [PMID: 19744468]
Thota, R.N.; Acharya, S.H.; Abbott, K.A.; Garg, M.L. Curcumin and long-chain Omega-3 polyunsaturated fatty acids for Prevention of type 2 Diabetes (COP-D): study protocol for a randomised controlled trial. Trials, 2016, 17(1), 565.
[] [PMID: 27894336]
Shah, L.; Gattacceca, F.; Amiji, M.M. CNS delivery and pharmacokinetic evaluations of DALDA analgesic peptide analog administered in Nano-sized oil-in-water emulsion formulation. Pharm. Res., 2014, 31(5), 1315-1324.
[] [PMID: 24297071]
Zaky, A.; Mahmoud, M.; Awad, D.; El Sabaa, B.M.; Kandeel, K.M.; Bassiouny, A.R. Valproic acid potentiates curcumin-mediated neuroprotection in lipopolysaccharide induced rats. Front. Cell. Neurosci., 2014, 8, 337.
[] [PMID: 25374508]
Zaky, A.; Bassiouny, A.; Farghaly, M.; El-Sabaa, B. M. A Combination of Resveratrol and Curcumin is Effective Against Aluminum Chloride-Induced Neuroinflammation in Rats. J. Alzheimers Dis, 2017. (Preprint) 1-15
Ramirez-Ramirez, V.; Macias-Islas, M.; Ortiz, G. G.; Pacheco-Moises, F.; Torres-Sanchez, E.; Sorto-Gomez, T.; Cruz-Ramos, J.; Orozco-Aviña, G.; Celis De La Rosa, A. Efficacy of fish oil on serum of TNFα, IL-1β, and IL-6 oxidative stress markers in multiple sclerosis treated with interferon beta-1b Oxid Med. Cell Longev., 2013, 2013
Lu, D-Y.; Tsao, Y-Y.; Leung, Y-M.; Su, K-P. Docosahexaenoic acid suppresses neuroinflammatory responses and induces heme oxygenase-1 expression in BV-2 microglia: implications of antidepressant effects for ω-3 fatty acids. Neuropsychopharmacology, 2010, 35(11), 2238-2248.
[] [PMID: 20668435]
Moon, D-O.; Kim, K-C.; Jin, C-Y.; Han, M-H.; Park, C.; Lee, K-J.; Park, Y-M.; Choi, Y.H.; Kim, G-Y. Inhibitory effects of eicosapentaenoic acid on lipopolysaccharide-induced activation in BV2 microglia. Int. Immunopharmacol., 2007, 7(2), 222-229.
[] [PMID: 17178390]
Zhao, Y.; Calon, F.; Julien, C.; Winkler, J.W.; Petasis, N.A.; Lukiw, W.J.; Bazan, N.G. 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
[] [PMID: 21246057]
Ortiz, G.G.; Pacheco-Moisés, F.P.; Gómez-Rodríguez, V.M.; González-Renovato, E.D.; Torres-Sánchez, E.D.; Ramírez-Anguiano, A.C. 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), 705-709.
[] [PMID: 23703110]
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), 154-161.
[] [PMID: 12127385]
Pradalier, A.; Bakouche, P.; Baudesson, G.; Delage, A.; Cornaille-Lafage, G.; Launay, J.M.; Biason, P. Failure of omega-3 polyunsaturated fatty acids in prevention of migraine: A double-blind study versus placebo. Cephalalgia, 2001, 21(8), 818-822.
[] [PMID: 11737007]
Mas, E.; Croft, K.D.; Zahra, P.; Barden, A.; Mori, T.A. Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation. Clin. Chem., 2012, 58(10), 1476-1484.
[] [PMID: 22912397]
Simopoulos, A.P. Omega-3 fatty acids in inflammation and autoimmune diseases. J. Am. Coll. Nutr., 2002, 21(6), 495-505.
[] [PMID: 12480795]
Xiao, L.; Ding, M.; Fernandez, A.; Zhao, P.; Jin, L.; Li, X. Curcumin alleviates lumbar radiculopathy by reducing neuroinflammation, oxidative stress and nociceptive factors. Eur. Cell. Mater., 2017, 33, 279-293.
[] [PMID: 28485773]
Lee, J.Y.; Shin, T.J.; Choi, J.M.; Seo, K.S.; Kim, H.J.; Yoon, T.G.; Lee, Y.S.; Han, H.; Chung, H.J.; Oh, Y.; Jung, S.J.; Shin, K.J. Antinociceptive curcuminoid, KMS4034, effects on inflammatory and neuropathic pain likely via modulating TRPV1 in mice. Br. J. Anaesth., 2013, 111(4), 667-672.
[] [PMID: 23719767]
Bulaj, G.; Ahern, M.M.; Kuhn, A.; Judkins, Z.S.; Bowen, R.C.; Chen, Y. Incorporating natural products, pharmaceutical drugs, self-care and digital/mobile health technologies into molecular-behavioral combination therapies for chronic diseases. Curr. Clin. Pharmacol., 2016, 11(2), 128-145.
[] [PMID: 27262323]
Tóth, A.; Boczán, J.; Kedei, N.; Lizanecz, E.; Bagi, Z.; Papp, Z.; Édes, I.; Csiba, L.; Blumberg, P.M. Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain. Brain Res. Mol. Brain Res., 2005, 135(1-2), 162-168.
[] [PMID: 15857679]
Tóth, A.; Czikora, A.; Pásztor, E.T.; Dienes, B.; Bai, P.; Csernoch, L.; Rutkai, I.; Csató, V.; Mányiné, I.S.; Pórszász, R.; Edes, I.; Papp, Z.; Boczán, J. Vanilloid receptor-1 (TRPV1) expression and function in the vasculature of the rat. J. Histochem. Cytochem., 2014, 62(2), 129-144.
[] [PMID: 24217926]
Kunder, S.K.; Bairy, L.K.; Arivazhahan, A. Effect of Sodium Valproate and Docosahexaenoic Acid on Pain in Rats. J. Clin. Diagn. Res., 2017, 11(3), FF05-FF08.
[] [PMID: 28511406]
Zhang, J.; Li, L.; Wang, J.; Xu, J.; Sun, D. Phase inversion of emulsions containing a lipophilic surfactant induced by clay concentration. Langmuir, 2013, 29(12), 3889-3894.
[] [PMID: 23445467]

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