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Cyclooxygenase expression and prostaglandin levels in central nervous system tissues during the course of chronic relapsing experimental autoimmune encephalomyelitis (EAE)

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Abstract

Objective

Multiple sclerosis (MS) and its animal counterpart experimental autoimmune encephalomyelitis (EAE) have a major inflammatory component that drives and orchestrates both diseases. One particular group of mediators are the prostaglandins (PGs), which we have previously shown, through quantitation and pharmacological intervention, to be closely involved in the pathology of MS and EAE. The aim of the current study was to determine the expression of the PG-generating cyclooxygenase (COX) enzymes and the profile of PGE2 and PGD2, in selected central nervous system (CNS) tissues, with the development of the chronic relapsing (CR) form of EAE. In particular, the work investigates the possible relationship between the expression of COX isoenzymes and PG levels during the neurological phases of CR EAE.

Methods

CR EAE was induced in Biozzi mice with inoculum containing lyophilised, syngeneic spinal cord emulsified in complete Freund’s adjuvant. The cerebral cortex, cerebellum and spinal cord were dissected from mice during the acute, remission and relapse stages of disease with a minimum of five animals per treatment. The expression of COX-1, COX-1b variant and COX-2, in pooled samples, was determined by Western blotting. PGE2 and PGD2 levels in extracted samples were measured using commercial enzyme immunoassay kits.

Results

COX-2 expression in spinal cords during acute disease remained unaltered and was in contrast to an enhancement of the enzyme, together with COX-1 and COX-1b, in all other sampled areas. PGE2 and PGD2 levels remained unchanged during the acute phase and the subsequent remission of symptoms. COX-1 and COX-1b expression was elevated in tissues during the relapse stage of CR EAE and concentrations of the prostanoids were markedly increased.

Conclusions

The study examines the implications of COX isoenzyme expression over the course of CR EAE and discusses the reported relationship between PGE2 and PGD2 in the instigation and resolution of CNS inflammation. Consideration is also given to the treatment of CR EAE and suggests that drugs designed to limit the inflammatory effects of the PGs should be administered prior to or during the relapse phase of the disease.

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References

  1. Kornek B, Lassmann H. Axonal pathology in multiple sclerosis: a historical note. Brain Pathol. 1999;9:651–6.

    Article  PubMed  CAS  Google Scholar 

  2. Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev. 2004;56:387–437.

    Article  PubMed  CAS  Google Scholar 

  3. Kotilinek LA, Westerman MA, Wang Q. Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity. Brain. 2008;131:651–64.

    Article  PubMed  Google Scholar 

  4. Ayoub SS, Colville-Nash PR, Willoughby DA, Botting RM. The involvement of a cyclooxygenase 1 gene-derived protein in the antinociceptive action of paracetamol in mice. Eur J Pharmacol. 2006;538:57–65.

    Article  PubMed  CAS  Google Scholar 

  5. Ueno R, Ishikawa Y, Nakayama T, Hayaishi O. Prostaglandin D2 induces sleep when microinjected into the preoptic area of conscious rats. Biochem Biophys Res Commun. 1982;109:576–82.

    Article  PubMed  CAS  Google Scholar 

  6. Milton AS, Wendlandt S. The effects of 4-acetamidophenol (paracetamol) on the temperature response of the conscious rat to the intracerebral injection of prostaglandin E, adrenaline and pyrogen. J Physiol. 1971;217:33P–34P.

    PubMed  CAS  Google Scholar 

  7. Ueno R, Narumiya S, Ogorochi T, Nakayama T, Ishikawa Y, Hayaishi O. Role of prostaglandin D2 in the hypothermia of rats caused by bacterial lipopolysaccharide. Proc Natl Acad Sci USA. 1982;79:6093–7.

    Article  PubMed  CAS  Google Scholar 

  8. Ayoub SS, Botting RM, Goorha S, Colville-Nash P, Willoughby D, Ballou LR. Acetominophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase-1 gene-derived protein. Proc Natl Acad Sci USA. 2004;101:11165–9.

    Article  PubMed  CAS  Google Scholar 

  9. Bolton C, Gordon D, Turk JL. A longitudinal study of the prostaglandin content of CNS tissues from guinea pigs with acute experimental allergic encephalomyelitis. Int J Immunopharmacol. 1984;6:155–61.

    Article  PubMed  CAS  Google Scholar 

  10. Bolton C, Turner AM, Turk JL. Prostaglandin levels in the cerebrospinal fluid from multiple sclerosis patients during relapse and remission. J Neuroimmunol. 1984;6:151–9.

    Article  PubMed  CAS  Google Scholar 

  11. Bolton C, Gordon D, Turk JL. Prostaglandin and thromboxane levels in central nervous tissues from rats during the induction and development of experimental allergic encephalomyelitis. Immunopharmacology. 1984;7:101–7.

    Article  PubMed  CAS  Google Scholar 

  12. Bolton C, Parker D, McLeod J, Turk JL. A study of the prostaglandin and thromboxane content of the central nervous tissues with the development of chronic relapsing allergic encephalomyelitis. J Neuroimmunol. 1986;10:201–8.

    Article  PubMed  CAS  Google Scholar 

  13. Bolton C, Cuzner ML. Modification of EAE by nonsteroidal anti-inflammatory drugs. In: Davison AN, Cuzner ML, editors. The suppression of experimental allergic encephalomyelitis and multiple sclerosis. London: Academic Press; 1980. p. 189–98.

    Google Scholar 

  14. Ovadia H, Paterson PY. Effect of indomethacin treatment upon actively-induced and transferred experimental allergic encephalomyelitis (EAE) in Lewis rats. Clin Exp Immunol. 1982;49:386–92.

    PubMed  CAS  Google Scholar 

  15. Prosiegel M, Neu I, Mallinger J, et al. Suppression of experimental autoimmune encephalomyelitis by dual cyclo-oxygenase and 5-lipoxygenase inhibition. Acta Neurol Scand. 1989;79:223–6.

    Article  PubMed  CAS  Google Scholar 

  16. Weber F, Meyermann R, Hempel K. Experimental allergic encephalomyelitis-prophylactic and therapeutic treatment with the cyclooxygenase inhibitor piroxicam (Feldene). Int Arch Allergy Appl Immunol. 1991;95:136–41.

    Article  PubMed  CAS  Google Scholar 

  17. Reder AT, Thapar M, Sapugay AM, Jensen MA. Prostaglandins and inhibitors of arachidonate metabolism suppress experimental allergic encephalomyelitis. J Neuroimmunol. 1994;54:117–27.

    Article  PubMed  CAS  Google Scholar 

  18. Bates D, Fawcett PR, Shaw DA, Weightman D. Trial of polyunsaturated fatty acids in non-relapsing multiple sclerosis. Br Med J. 1977;2:932–3.

    Article  PubMed  CAS  Google Scholar 

  19. Mertin J, Stackpoole A. Suppression by essential fatty acids of experimental allergic encephalomyelitis is abolished by indomethacin. Prostaglandins Med. 1978;1:283–6.

    Article  PubMed  CAS  Google Scholar 

  20. Gallai V, Sarchielli P, Trequattrini A, Murasecco D. Supplementation of polyunsaturated fatty acids in multiple sclerosis. Ital J Neurol Sci. 1992;13:401–7.

    Article  PubMed  CAS  Google Scholar 

  21. Harbige LS, Layward L, Morris-Downes MM, Dumonde DC, Amor S. The protective effects of omega-6 fatty acids in experimental autoimmune encephalomyelitis (EAE) in relation to transforming growth factor-beta 1 (TGF-beta1) up-regulation and increased prostaglandin E2 (PGE2) production. Clin Exp Immunol. 2000;122:445–52.

    Article  PubMed  CAS  Google Scholar 

  22. Smith WL, DeWitt DL, Graves RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem. 2000;69:145–82.

    Article  PubMed  CAS  Google Scholar 

  23. Kam PC, See AU. Cyclo-oxygenase isoenzymes: physiological and pharmacological role. Anaesthesia. 2000;55:442–9.

    Article  PubMed  CAS  Google Scholar 

  24. Shaftel SS, Olschowka JA, Hurley SD, Moore AH, O’Banion MK. COX-3: a splice variant of cyclooxygenase-1 in mouse neural tissue and cells. Brain Res Mol Brain Res. 2003;119:213–5.

    Article  PubMed  CAS  Google Scholar 

  25. Minghetti L. Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol. 2004;63:901–10.

    PubMed  CAS  Google Scholar 

  26. Rose JW, Hill KE, Watt HE, Carlson NG. Inflammatory cell expression of cyclooxygenase-2 in the multiple sclerosis lesion. J Neuroimmunol. 2004;149:40–9.

    Article  PubMed  CAS  Google Scholar 

  27. Carlson NG, Hill KE, Tsunoda I, Fujinami RS, Rose JW. The pathologic role for COX-2 in apoptotic oligodendrocytes in virus induced demyelinating disease: implications for multiple sclerosis. J Neuroimmunol. 2006;174:21–31.

    Article  PubMed  CAS  Google Scholar 

  28. Yiangou Y, Facer P, Durrenberger P, et al. COX-2, CB2, P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 2006;6:12–26.

    Article  PubMed  Google Scholar 

  29. Deininger MH, Schluesener HL. Cyclooxygenase-1 and -2 are differentially localized to microgila and endothelium in rat EAE and glioma. J Neuroimmunol. 1999;95:202–8.

    Article  PubMed  CAS  Google Scholar 

  30. Marusic S, Leach MW, Pelker JW, et al. Cytosolic phospholipase A2 alpha-deficient mice are resistant to experimental autoimmune encephalomyelitis. J Exp Med. 2005;202:841–51.

    Article  PubMed  CAS  Google Scholar 

  31. Hanel AM, Lands WEM. Modification of anti-inflammatory drug effectiveness by ambient lipid peroxides. Biochem Pharmacol. 1982;31:3307–11.

    Article  PubMed  CAS  Google Scholar 

  32. Zielasek J, Hartung HP. Molecular mechanisms of microglial activation. Adv Neuroimmunol. 1996;6:191–220.

    Article  PubMed  CAS  Google Scholar 

  33. Moon C, Ahn M, Wie MB, et al. Phenidone, a dual inhibitor of cyclooxygenase and lipoxygenase, ameliorates rat paralysis in experimental autoimmune encephalomyelitis by suppressing its target enzymes. Brain Res. 2005;1035:206–10.

    Article  PubMed  CAS  Google Scholar 

  34. Miyamoto K, Miyake S, Mizuno M, Oka N, Kusunoki S, Yamamura T. Selective COX-2 inhibitor celecoxib prevents experimental autoimmune encephalomyelitis through COX-2-independent pathway. Brain. 2006;129:1984–92.

    Article  PubMed  Google Scholar 

  35. Muthian G, Raikwar HP, Johnson C, et al. COX-2 inhibitors modulate IL-12 signalling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis. J Clin Immunol. 2006;26:73–85.

    Article  PubMed  CAS  Google Scholar 

  36. Choi SH, Aid S, Bosetti F. The distinct role of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci. 2009;30:174–81.

    Article  PubMed  CAS  Google Scholar 

  37. Baker D, O’Neill JK, Gschmeissner SE, Wilcox CE, Butter C, Turk JL. Induction of chronic relapsing experimental allergic encephalomyelitis in Biozzi mice. J Neuroimmunol. 1990;28:261–70.

    Article  PubMed  CAS  Google Scholar 

  38. Zeis T, Kinter J, Herrero-Herranz E, Weissert R, Schaeren-Wiemers N. Gene expression analysis of normal appearing brain tissue in an animal model for multiple sclerosis revealed grey matter alterations, but only minor white matter changes. J Neuroimmunol. 2008;205:10–9.

    Article  PubMed  CAS  Google Scholar 

  39. ‘t Hart BA, Gran B, Weissert R. EAE: imperfect but useful models of multiple sclerosis. Trends Mol Med. 2011; 17: 119-25.

  40. Bolton C, O’Neill JK, Allen SJ, Baker D. Regulation of chronic relapsing experimental allergic encephalomyelitis by endogenous and exogenous glucocorticoids. Int Arch Allergy Immunol. 1997;114:74–80.

    Article  PubMed  CAS  Google Scholar 

  41. Bolton C. The translation of drug efficacy from in vivo models to human disease with special reference to experimental autoimmune encephalomyelitis and multiple sclerosis. Inflammopharmacol. 2007;15:183–7.

    Article  CAS  Google Scholar 

  42. Stables MJ, Gilroy DW. Old and new generation lipid mediators in acute inflammation and resolution. Prog Lipid Res. 2011;50:35–51.

    Article  PubMed  CAS  Google Scholar 

  43. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.

    Article  PubMed  CAS  Google Scholar 

  44. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970;227:680–5.

    Article  PubMed  CAS  Google Scholar 

  45. Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets. Proceedure and some applications. Proc Natl Acad Sci USA. 1979;79:4350–4.

    Article  Google Scholar 

  46. De Blas AL, Cherwinski HM. Detection of antigens on nitrocellulose paper immunoblots with monoclonal antibodies. Anal Biochem. 1983;133:214–9.

    Article  PubMed  Google Scholar 

  47. Frazer HE, Wisdom GB. Detection of auto-antigens by immunoblotting using a peroxidase-anti-peroxidase complex. J Immunol Method. 1985;80:221–5.

    Article  CAS  Google Scholar 

  48. Ayoub SS, Yazid S, Flower RJ. Increased susceptibility of annexin-A1 null mice to nociceptive pain is indicative of a spinal antinociceptive role of annexin-A1. Br J Pharmacol. 2008;154:1135–42.

    Article  PubMed  CAS  Google Scholar 

  49. Bonta I, Parnham M. Prostaglandins and chronic inflammation. Biochem Pharmacol. 1978;27:1611–5.

    Article  PubMed  CAS  Google Scholar 

  50. Lawrence T, Willoughby DA, Gilroy DW. Anti-inflammatory lipid mediators and insight into the resolution of inflammation. Nat Rev Immunol. 2002;10:787–95.

    Article  Google Scholar 

  51. Leslie JB, Watkins WD. Eicosanoids in the central nervous system. J Neurosurg. 1985;63:659–68.

    Article  PubMed  CAS  Google Scholar 

  52. Kaufmann WE, Andreasson KI, Isakson PC, Worley PF. Cyclooxygenases and the central nervous system. Prostaglandins. 1997;54:601–4.

    Article  PubMed  CAS  Google Scholar 

  53. Niwa K, Araki E, Morham SG, Ross ME, Iadecola C. Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J Neurosci. 2000;20:763–70.

    PubMed  CAS  Google Scholar 

  54. Yang H, Chen C. Cyclooxygenase-2 in synaptic signalling. Curr Pharm Des. 2008;14:1443–51.

    Article  PubMed  CAS  Google Scholar 

  55. Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA. 2002;99:3926–31.

    Article  Google Scholar 

  56. Dinchuk JE, Liu RQ, Trzaskos JM. COX-3: in the wrong frame in mind. Immunol Lett. 2003;86:121.

    Article  PubMed  CAS  Google Scholar 

  57. Kis B, Snipes JA, Gaspar T, Lenzser G, Tulbert CD, Busija DW. Cloning of cyclooxygenase-1b (putative COX-3) in mouse. Inflamm Res. 2006;55:274–8.

    Article  PubMed  CAS  Google Scholar 

  58. Allen SJ, Baker D, O’Neill JK, Davison AN, Turk JL. Isolation and characterisation of cells infiltrating the spinal cord during the course of chronic relapsing experimental allergic encephalomyelitis in the Biozzi AB/H mouse. Cell Immunol. 1993;146:335–50.

    Article  PubMed  CAS  Google Scholar 

  59. Papadopoulos D, Pham-Dinh D, Reynolds R. Axon loss is responsible for chronic neurological deficit following inflammatory demyelination in the rat. Exp Neurol. 2006;197:373–85.

    Article  PubMed  CAS  Google Scholar 

  60. Jackson SJ, Lee J, Nikodemova M, Fabry Z, Duncan ID. Quantification of myelin and axon pathology during relapsing progressive experimental autoimmune encephalomyelitis in the Biozzi ABH mouse. J Neuropathol Exp Neurol. 2009;68:616–25.

    Article  PubMed  CAS  Google Scholar 

  61. Bosetti F, Langenbach R, Weerasinghe GR. Prostaglandin E2 and microsomal prostaglandin E synthase-2 expression are decreased in the cyclooxygenase-2-deficient mouse brain despite compensatory induction of cyclooxygenase-1 and Ca2+-dependent phospholipase A2. J Neurochem. 2004;91:1389–97.

    Article  PubMed  CAS  Google Scholar 

  62. Murakami M, Kudo I. Recent advances in molecular biology and physiology of the prostaglandin E2-biosynthetic pathway. Prog Lipid Res. 2004;43:3–35.

    Article  PubMed  CAS  Google Scholar 

  63. Choi SH, Langenbach R, Bosetti F. Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-kappaB pathway and downstream enzymes involved in prostaglandin biosynthesis. J Neurochem. 2006;98:801–11.

    Article  PubMed  CAS  Google Scholar 

  64. MacKenzie-Graham A, Tinsley MR, Shah KP, et al. Cerebellar cortical atrophy in experimental autoimmune encephalomyelitis. Neuroimage. 2006;32:1016–23.

    Article  PubMed  Google Scholar 

  65. Herrero-Herranz E, Pardo LA, Gold R, Linker RA. Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: implications for multiple sclerosis. Neurobiol Dis. 2008;30:162–73.

    Article  PubMed  CAS  Google Scholar 

  66. Yermakova AV, Rollins J, Callahan LM, Rogers J, O’Banion MK. Cyclooxygenase-1 in human Alzheimer and control brain: quantitative analysis of expression by microglia and CA3 hippocampal neurons. J Neuropathol Exp Neurol. 1999;58:1135–46.

    Article  PubMed  CAS  Google Scholar 

  67. Maihofner C, Tegeder I, Euchenhofer C, et al. Localisation and regulation of cyclo-oxygenase-1 and -2 and neuronal nitric acid synthase in mouse spinal cord. Neuroscience. 2000;101:1093–108.

    Article  PubMed  CAS  Google Scholar 

  68. Deininger MH, Bekure-Nemariam K, Trautmann M, Morgalla R, Meyermann R, Schluesener HJ. Cyclooxygenase-1 and -2 in brains of patients who died with sporadic Creutzfeldt-Jakob disease. J Mol Neurosci. 2003;20:25–30.

    Article  PubMed  CAS  Google Scholar 

  69. Minghetti L, Pocchiari M. Cyclooxygenase-2, prostaglandin E2, and microglial activation in prion diseases. Int Rev Neurobiol. 2007;82:265–75.

    Article  PubMed  CAS  Google Scholar 

  70. Almer G, Kikuchi H, Teimann P, Przedborski S. Is prostaglandin E2 a pathogenic factor in amytrophic lateral sclerosis? Ann Neurol. 2006;59:980–3.

    Article  PubMed  CAS  Google Scholar 

  71. Teismann P, Tieu K, Choi DK, Wu DC, et al. Cyclooxygenase is instrumental in Parkinson’s disease neurodegeneration. Proc Natl Acad Sci USA. 2003;100:5473–8.

    Article  PubMed  CAS  Google Scholar 

  72. Aloisi F, Serafini B, Adorini L. Glia-T cell dialogue. J Neuroimmunol. 2000;107:111–7.

    Article  PubMed  CAS  Google Scholar 

  73. Mannie MD, Prevost KD, Marinakis CA. Prostaglandin E2 promotes the induction of anergy during T helper cell recognition of myelin basic protein. Cell Immunol. 1995;160:132–8.

    Article  PubMed  CAS  Google Scholar 

  74. Liang X, Wu L, Hand T, Andreasson K. Prostaglandin D2 mediates neuronal protection via the DP1 receptor. J Neurochem. 2005;92:477–86.

    Article  PubMed  CAS  Google Scholar 

  75. Mohri I, Taniike M, Taniguchi H, et al. Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher mice. J Neurosci. 2006;26:4383–93.

    Article  PubMed  CAS  Google Scholar 

  76. Scher JU, Pillinger MH. The anti-inflammatory effects of prostaglandins. J Investig Med. 2009;57:703–8.

    PubMed  CAS  Google Scholar 

  77. Kihara Y, Matsushita T, Kita Y, et al. Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis. Proc Natl Acad Sci USA. 2009; 106:21807-12.

    Google Scholar 

  78. Serhan CN, Chiang N. Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus. Br J Pharmacol. 2009;153:S200–15.

    Article  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the financial support of the William Harvey Research Foundation and The Leverhulme Trust for provision of funding for Dr Ayoub.

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Authors and Affiliations

  1. Centre for Biochemical Pharmacology, William Harvey Research Institute, St. Bartholomew’s and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK

    Samir S. Ayoub & Sabih-Ul Hassan

  2. Centre for Translational Medicine and Therapeutics, Second Floor, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK

    Elizabeth G. Wood

  3. Neuroimmunology Unit, Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4, Newark Street, London, E12 AT, UK

    Christopher Bolton

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  1. Samir S. Ayoub
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  2. Elizabeth G. Wood
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  3. Sabih-Ul Hassan
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  4. Christopher Bolton
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Correspondence to Christopher Bolton.

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Responsible Editor: Graham Wallace.

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Ayoub, S.S., Wood, E.G., Hassan, SU. et al. Cyclooxygenase expression and prostaglandin levels in central nervous system tissues during the course of chronic relapsing experimental autoimmune encephalomyelitis (EAE). Inflamm. Res. 60, 919–928 (2011). https://doi.org/10.1007/s00011-011-0352-3

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