The potential effects of hemp seed/evening primrose oils on the mammalian target of rapamycin complex 1 and interferon-gamma genes expression in experimental autoimmune encephalomyelitis

Soheila Rezapour-Firouzi , Shahram Shahabi, Adel Mohammadzadeh , Ali Asgar Tehrani, Fatemeh Kheradmand, Ebrahim Mazloomi

Abstract


The mammalian target of rapamycin (mTOR) has a fundamental role in the metabolism, growth, and regulation of the immune system. The interferon gamma (IFN-γ)derived from T helper 1 (Th1) cells is a prominent pro-inflammatory cytokine in multiple sclerosis (MS) and its animal model, the experimental autoimmune encephalomyelitis (EAE). Due to the exclusive role of rapamycin (RAPA) in mTOR complex 1 (mTORC1) inhibition, essentially Th1 differentiation and IFN-γ production, we evaluated the potential therapeutic effects of hemp seed/evening primrose oils (HSO/EPO) in comparison with RAPA administration in EAE. To evaluate the therapeutic effects of EPO/HSO supplement in comparison with RAPA, EAE was induced using myelin oligodendrocyte glycoprotein (MOG) peptide and complete Freund's adjuvant in C57BL/6 mice. The weight, clinical score, and histological findings were evaluated. Total mRNA was extracted from local lymph nodes and qRT-PCR was used for the purpose of the genes expression level of regulatory associated protein of TORC1 (RAPTOR) and IFN-γ. Our results indicated that the relative expression of RAPTOR and IFN-γ genes were significantly reduced in HSO/EPO, RAPA, and RAPA + HSO/EPO treated groups in comparison with the untreated group. Interestingly, histological findings have shown that the HSO/EPO treated group remarkably regenerated the myelin sheath, but this did not occur in the case of RAPA or combined RAPA and HSO/EPO treated groups. Our findings suggeste that HSO/HPO can be used as a potent immunomodulator and as a good candidate for re-myelination and downregulation of immune response for treatment of MS.


Keywords


Keywords: Experimental autoimmune encephalomyelitis; Inflammation; Multiple sclerosis; Myelin sheath; Sirolimus.

Full Text:

PDF

References


Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009;122(Pt 20):3589-3594.

Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med. 2008;205(3):565-574.

Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30(6):832-844.

Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S, Killeen N, et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity. 2010;32(6):743-753.

Kopf H, de la Rosa GM, Howard OM, Chen X. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol. 2007;7(13):1819-1824.

Korn T, Anderson AC, Bettelli E, Oukka M. The dynamics of effector T cells and Foxp3+ regulatory T cells in the promotion and regulation of autoimmune encephalomyelitis. J Neuroimmunol. 2007;191(1-2):51-60.

Ghadirian P, Jain M, Ducic S, Shatenstein B, Morisset R. Nutritional factors in the aetiology of multiple sclerosis: a case-control study in Montreal, Canada. Int J Epidemiol. 1998;27(5):845-852.

van Meeteren ME, Teunissen CE, Dijkstra CD, van Tol EA. Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005;59(12):1347-1361.

Gallai V, Sarchielli P, Trequattrini A, Franceschini M, Floridi A, Firenze C, et al. Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids. J Neuroimmunol. 1995;56(2):143-153.

Simopoulos AP, Leaf A, Salem NJr. Workshop statement on the essentiality of and recommended dietary intakes for Omega-6 and Omega-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids. 2000;63(3):119-121.

Rezapour-Firouzi S, Arefhosseini SR, Mehdi F, Mehrangiz EM, Baradaran B, Sadeghihokmabad E, et al. Immunomodulatory and therapeutic effects of Hot-nature diet and co-supplemented hemp seed, evening primrose oils intervention in multiple sclerosis patients. Complement Ther Med. 2013;21(5):473-480.

Rezapour-Firouzi S, Arefhosseini SR, Ebrahimi-Mamaghani M, Farhoudi M, Baradaran B, Ali TM, et al. Erythrocyte membrane fatty acids in multiple sclerosis patients and hot-nature dietary intervention with co-supplemented hemp-seed and evening-primrose oils. Afr J Tradit Complement Altern Med. 2013;10(6):519-527.

Hassam AG, Rivers JP, Crawford MA. Metabolism of gamma-linolenic acid in essential fatty acid-deficient rats. J Nutr. 1977;107(4):519-524.

Hassam AG. The influence of alpha-linolenic acid (18: 3omega3) on the metabolism of gamma-linolenic acid (18: 3omega6) in the rat. Br J Nutr. 1977;38(1):137-140.

Mohammadian M, Zeynali S, Azarbaijani AF, Khadem Ansari MH, Kheradmand F. Cytotoxic effects of the newly-developed chemotherapeutic agents 17-AAG in combination with oxaliplatin and capecitabine in colorectal cancer cell lines. Res Pharm Sci. 2017;12(6):517-525.

Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003;35(3 Suppl):7S-14S.

Rahn EJ, Iannitti T, Donahue RR, Taylor BK. Sex differences in a mouse model of multiple sclerosis: neuropathic pain behavior in females but not males and protection from neurological deficits during proestrus. Biol Sex Differ. 2014;5(1):4-21.

Mohammadzadeh A, Pourfathollah AA, Shahrokhi S, Fallah A, Tahoori MT, Amari A, et al. Evaluation of AD-MSC (adipose-derived mesenchymal stem cells) as a vehicle for IFN-β delivery in experimental autoimmune encephalomyelitis. Clin Immunol. 2016;169:98-106.

Benson JM, Campbell KA, Guan Z, Gienapp IE, Stuckman SS, Forsthuber T, et al. T-cell activation and receptor downmodulation precede deletion induced by mucosally administered antigen. J Clin Invest. 2000;106(8):1031-1038.

Lisi L, Aceto P, Navarra P, Dello Russo C. mTOR kinase: a possible pharmacological target in the management of chronic pain. Biomed Res Int. 2015;2015. Article ID: 394257.

Mangalam AK, Luo N, Luckey D, Papke L, Hubbard A, Wussow A, et al. Absence of IFN-gamma increases brain pathology in experimental autoimmune encephalomyelitis-susceptible DRB1*0301.DQ8 HLA transgenic mice through secretion of proinflammatory cytokine IL-17 and induction of pathogenic monocytes/microglia into the central nervous system. J Immunol. 2014;193(10):4859-4870.

Yuan JS, Reed A, Chen F, Stewart CN, Jr. Statistical analysis of real-time PCR data. BMC Bioinformatics. 2006;7:85.

Machado AM, de Souza WM, de Padua M, da Silva Rodrigues Machado AR, Figueiredo LT. Development of a one-step SYBR Green I real-time RT-PCR assay for the detection and quantitation of Araraquara and Rio Mamore hantavirus. Viruses. 2013;5(9):2272-2281.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-408.

Matsushima GK, Morell P. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol. 2001;11(1):107-116.

Ben-Nun A, Mendel I, Bakimer R, Fridkis-Hareli M, Teitelbaum D, Arnon R, et al. The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: effect of copolymer 1 on MOG-induced disease. J Neurol. 1996;243(4 Suppl 1):S14-S22.

Callaway JC. Hempseed as a nutritional resource: An overview. Euphytica. 2004;140(1-2):65-72.

Matthaus B, Brühl L. Virgin hemp seed oil: An interesting niche product. Eur J Lipid Sci Technol. 2008;110(7):655-661.

Okuyama H, Kobayashi T, Watanabe S. Dietary fatty acids the N-6/N-3 balance and chronic elderly diseases. Excess linoleic acid and relative N-3 deficiency syndrome seen in Japan. Prog Lipid Res. 1996;35(4):409-457.

Calder PC, Zurier RB. Polyunsaturated fatty acids and rheumatoid arthritis. Curr Opin Clin Nutr Metab Care. 2001;4(2):115-121.

Oomah BD, Busson M, Godfrey DV, Drover JCG. Characteristic of hemp (Cannabis sativa L.) seed oil. Food Chemistry. 2002;76(1):33-43.

Christie WW. The analysis of evening primrose oil. Ind Crops Prod. 1999;10(2):73-83.

Taylor M. Alternative medicine and the perimenopause an evidence-based review. Obstet Gynecol Clin North Am. 2002;29(3):555-573.

Horrobin DF. Multiple sclerosis: the rational basis for treatment with colchicine and evening primrose oil. Med Hypotheses. 1979;5(3):365-378.

Merkel S, Mogilevskaja N, Mengel M, Haller H, Schwarz A. Side effects of sirolimus. Transplant Proc. 2006;38(3):714-715.

Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature. 2013;496(7446):513-517.

Rezapour-Firouzi S. Herbal Oil Supplement With Hot-Nature Diet for Multiple Sclerosis. In: Watson RR, Killgore WDS, editors. Nutrition and Lifestyle in Neurological Autoimmune Diseases. 1st ed. Academic Press; 2017. pp. 229-245.

Yang K, Shrestha S, Zeng H, Karmaus PW, Neale G, Vogel P, et al. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity. 2013;39(6):1043-1056.

Lassmann H, Bruck W, Lucchinetti C, Rodriguez M. Remyelination in multiple sclerosis. Mult Scler. 1997;3(2):133-136.

Pavlakis M, Goldfarb-Rumyantzev AS. Diabetes after transplantation and sirolimus: what's the connection? J Am Soc Nephrol. 2008;19(7):1255-1256.

Sachs HH, Bercury KK, Popescu DC, Narayanan SP, Macklin WB. A new model of cuprizone-mediated demyelination/remyelination. ASN Neuro. 2014;6(5). pii:1759091414551955.

Yehuda S, Rabinovitz S, Mostofsky DI. Essential fatty acids and the brain: from infancy to aging. Neurobiol Aging. 2005;26(Suppl 1):98-102.

Brown NF, Stefanovic-Racic M, Sipula IJ, Perdomo G. The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes. Metabolism. 2007;56(11):1500-1507.

Zivkovic AM, German JB, Lebrilla CB, Mills DA. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4653-4658.

Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531-562.

Yuan LF, Li GD, Ren XJ, Nian H, Li XR, Zhang XM. Rapamycin ameliorates experimental autoimmune uveoretinitis by inhibiting Th1/Th2/Th17 cells and upregulating CD4+CD25+ Foxp3 regulatory T cells. Int J Ophthalmol. 2015;8(4):659-664.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.