THE INFLUENCE OF FUNCTIONAL POLYMORPHISM IN THE GALANIN PROMOTOR ON GLATIRAMER ACETATE EFFICACY IN EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

DOI: https://doi.org/None

I.N. Abdurasulova (1), V.I. Lioudyno (1), Y.L. Zitnukhin (1), A.V. Matsulevich (1), G.N. Bisaga (2), V.M. Klimenko (1) 1 -Federal State Budgetary Scientific Institution Institute of Experimental medicine, Acad. Pavlov str., 12, Saint-Petersburg, 197376, Russian Federation; 2 -S.M. Kirov Military Medical Academy, Acad. Lebedev str., 6, Saint-Petersburg, 194044, Russian Federation

Introduction. Glatiramer acetate (GA, copaxone) – is an immunomodulatory drug, used for reducing the progression of multiple sclerosis. The absence of optimal therapeutic effect in some cases determines the necessity to search the prognostic markers of GA efficacy. It is known that reducing of relapses frequency and disability progression may be observed in 60–70% GA-treated patients. It could be suggested that neuropeptide galanin is one of the genes-candidates, influencing to individual response for GA, because the increase of galanin gene expression is correlated with the intensity of reparative processes in injured brain. The aim of the study. Was the comparative analysis of GA efficiency in Wistar rats carried the variants of the galanin gene with different level of the transcriptional activity. Methods. The rat model of multiple sclerosis, experimental allergic encephalomyelitis (EAE) was used. The signs of a vulnerability to the induction of EAE and disease severity were compared. The serum background levels of proinflammatory cytokines IL1β and IL17A as well as EAE-induced dynamics of its content were measured by ELISA. Results. The maximal treatment response to GA was obtained in homozygous carriers of ACT allele, the polymorphic variant with the high level of the transcriptional activity. It was revealed also the different dynamics of IL1β level in GA treated homozygous carriers of ACT allele and homozygous carriers of GTG allele during the EAE. The basal level of IL1β was significantly lower in ACT homozygotes compared with the GTG homozygotes. Conclusion. These findings provide the new aspects of GA pharmacogenetics and point to the relevance of the clinical studies led to elucidate the association between the polymorphic variants of the galanin gene and treatment response to GA in patients with the multiple sclerosis.
Keywords: 
multiple sclerosis, glatiramer acetate, pharmacogenetics, cytokines
Список литературы: 
  1. Boyko A.N., Davydovskaya M.V., Demina T.L., Lashh N.Yu., Ovcharov V.V., Popova E.V., Popova N.F., Romashkin A.V., Boyko O.V., Hachanova N.V., Sharanova S.N., Shhur S.G., Gusev E.I. E`ffektivnost` i perenosimost` glatiramera acetata (kopaksona) pri dlitel`nom ispol`zovanii: 10-letniy opyt Moskovskogo gorodskogo centra rasseyannogo skleroza. Zhurn. nevrol. i psihiat. im. S.S. Korsakova. 2012; 112 (2): 86–92. [Boiko A.N., Davydovskaya M.V., Demina T.L., Lashch N.Yu., Ovcharov V.V., Popova E.V., Popova N.F., Romashkin A.V., Boiko O.V., Khachanova N.V., Sharanova S.N., Shchur S.G., Gusev E.I. Efficacy and tolerability of long-term using of glatimer acetate (copaxone): a 10 year-study in the Moscow Municipal Multiple Sclerosis center. Zh. nevrol. psikhiatr. Im. S.S. Korsakova. 2012; 112 (2): 86–92 (in Russian)]
  2. Peresedova A.V., Zavalishin I.A., Adarcheva L.S., Askarova L.Sh., Zaharova M.N., Eliseeva D.D, Niyazbekova A.S, Stoyda N.I, Trifonova O.V. Glatiramera acetat (Kopakson) v lechenii rasseyannogo skleroza. Rezul`taty dlitel`nogo primeneniya: voznikayushhie voprosy i napravleniya dal`neyshih issledovaniy. Nervnye bolezni. 2012; 4: 26–30. [Peresedova A.V., Zavalishin I.A., Adarcheva L.S., Askarova L.Sh., Zakharova M.N., Eliseeva D.D., Niyazbekova A.S., Stoida N.I., Trifonova O.V. Glatiramera acetat (Kopakson) v lechenii rassejannogo skleroza. Rezul’taty dlitel’nogo primenenija: voznikajushhie voprosy i napravlenija dal’nejshih issledovanij. Nervnye bolezni. 2012; 4: 26–30 (in Russian)]
  3. Fusco C., Andreone V., Coppola G., Luongo V., Guerini F., Pace E., Florio C., Pirozzi G., Lanzillo R., Ferrante P., Vivo P., Mini M., Macri M., Orefice G., Lombardi M.L. HLA-DRB1*1501 and response to copolymer-1 therapy in relapsing-remitting multiple sclerosis. Neurology. 2001; 57 (11): 1976–9.
  4. Bornstein M., Miller A., Slagle S., Weitzman M., Crystal H., Drexler E., Keilson M., Merriam A., Wassertheil-Smoller S., Spada V., Weiss W., Arnon R., Jacobsohn I., Teitelbaum D., Sela M. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N. Engl. J. Med. 1987; 317: 408–14.
  5. Careva E.Yu., Kulakova O.G., Makarycheva O.Yu., Boyko A.N., Shhur S.G., Lashh N.Yu., Popova N.F., Gusev E.I., Bashinskaya V.V., L`vov D.V., Favorov A.V., Ochs M.F., Favorova O.O. Farmakogenomika rasseyannogo skleroza: associaciya polimorfizma genov immunnogo otveta s e`ffektivnost`yu lecheniya kopaksonom. Mol. biol. 2011; 45 (6): 963–72. [Tsareva E.Yu., Kulakova O.G., Makarycheva O.Yu., Boiko A.N., Shchur S.G., Lashch N.Yu., Popova N.F., Gusev E.I., Bashinskaya V.V., Lvov D.V., Favorov A.V., Ochs M.F., Favorova O.O. Pharmacogenomics of multiple sclerosis: association of immune response genes polymorphism with copaxone treatment efficacy. Mol. boil. 2011; 45 (6): 963–72 (in Russian)]
  6. Grossman I., Avidan N., Singer C., Goldstaub D., Hayardeny L., Eyal E., Ben-Asher E., Paperna T., Pe’er I., Lancet D., Beckmann J., Miller A. Pharmacogenetics of glatiramer acetate therapy for multiple sclerosis reveals drug-response markers. Pharmacogenet Genomics. 2007; 17 (8): 657–66.
  7. Mahurkar S., Suppiah V., O’Doherty C. Pharmacogenomics of interferon beta and glatiramer acetate response: A review of the literature. Autoimmun Rev. 2014; 13: 178–86.
  8. Hökfelt T., Wiesenfeld-Hallin Z., Vil-lar M., Melander T. Increase of galanin-like immunoreactivity in rat dorsal root ganglion cells after peripheral axotomy. Neurosci Lett. 1987; 83: 217–20.
  9. De Michele M., Sancesario G., Toni D., Ciuffoli A., Bernardi G., Sette G. Specific expression of galanin in the peri-infarct zone after permanent focal cerebral ischemia in the rat. Regul Pept. 2006; 134 (1): 38–45.
  10. Theodorsson A., Holm L., Theodorsson E. Hypothermia-induced increase in galanin concentrations and ischemic neuroprotection in the rat brain. Neuropeptides. 2008; 42 (1): 79–87.
  11. Wraith D.C., Pope R., Butzkueven H., Holder H., Vanderplank P., Lowrey P., Daye M.J., Gundlachc A.L., Kilpatrickc T.J., Scoldingd N., Wynick D. A role for galanin in human and experimental inflammatory demyelination. Proc. Natl. Acad. Sci USA. 2009; 106 (36): 15466–71.
  12. Lioudyno V.I., Aksenova T.S., Abdurasulova I.N., Klimenko V.M. Allelic variants of the galanin gene in Wistar rats. Neurochemical J. 2014; 8 (1): 11–6.
  13. Abdurasulova I.N., Serdyuk S.E., Gmiro V.E. Comparative study of preventive and therapeutic effects of IEM-1966 and memantine in rats with experimental allergic encephalomyelitis. Bull. Exp. Biol. Med. 2007; 144 (2): 217–20.
  14. Sela M., Teitelbaum D. Glatiramer acetate in the treatment of multiple sclerosis. Expert Opin Pharmacother. 2001; 2 (7): 1149–65.
  15. Serebryanaya N.B., Karpenko M.N., Zhitnuhin Yu.L., Bisaga G.N., Abdurasulova I.N. Issledovanie protektivnogo deystviya preparata ferrovir pri ostrom e`ksperimental`nom allergicheskom e`ncefalomielite. Citokiny i vospalenie. 2010; 9 (1): 33–9. [Serebrjanaya N.B., Karpenko M.N., Zhitnuhin Yu.L., Bisaga G.N., Abdurasulova I.N. Issledovanie protektivnogo dejstvija preparata ferrovir pri ostrom jeksperimental’nom allergicheskom jencefalomielite. Cytokines & Inflammation. 2010; 9 (1): 33–9 (in Russian)]
  16. Unschuld P., Ising M., Erhardt A., Lucae S., Kohli M., Kloiber S., Salyakina D., Thoeringer C., Kern N., Lieb R., Uhr M., Binder E., Müller-Myhsok B., Holsboer F., Keck M.E. Polymorphisms in the galanin gene are associated with symptom-severity in female patients suffering from panic disorder. J. Affect Disord. 2008; 105 (1–3): 177–84.
  17. Bakshi S., Chalifa-Caspi V., Plaschkes I., Perevozkin I., Gurevich M., Schwartz R. Gene expression analysis reveals functional pathways of glatiramer acetate activation. Expert Opin. Ther. Targets. 2013; 17 (4): 351–62.
  18. Jee Y., Liu R., Bai X.F., Campagnolo D.I., Shi F.D., Vollmer T.L. Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis? Int. Immunol. 2006; 18 (4): 537–44.
  19. Sutton C., Brereton C., Keogh B., Mills K.H., Lavelle E.C. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J. Exp. Med. 2006; 203 (7): 1685–91.
  20. Mason J.L., Suzuki K., Chaplin D.D., Matsushima G.K. Interleukin-1beta promotes repair of the CNS. J. Neurosci. 2001; 21 (18): 7046–52.
  21. Ziemssen T., Kümpfel T., Klinkert W.E., Neuhaus O., Hohlfeld R. Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain. 2002; 125 (Pt. 11): 2381–91.
  22. Aharoni R., Eilam R., Domev H., Labunskay G., Sela M., Arnon R. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc. Natl. Acad. Sci USA. 2005; 102 (52): 19045–50.