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01-11-2009 | Basic Neurosciences, Genetics and Immunology - Review Article

Neuroprotection and neurogeneration in MS and its animal model EAE effected by glatiramer acetate

Authors: Ruth Arnon, Rina Aharoni

Published in: Journal of Neural Transmission | Issue 11/2009

Abstract

It is by now established that multiple sclerosis (MS) is not simply an autoimmune disease and that in addition to inflammation and demyelination, axonal injury and neuronal loss underlie the accumulation of disability and the disease progression. Specific treatment strategies should thus target the injury sites at the central nervous system (CNS) to interfere with both neuroinflammation and neurodegeneration. Glatiramer acetate (GA Copaxone^®, Copolymer 1), an approved drug for the treatment of multiple sclerosis, was shown earlier to act as an anti-inflammatory and immunomodulatory agent. In this mini-review its effect on neuroprotection, neurogenesis and on the remyelination process is delineated in the EAE model. The plausible mechanism underlying this multifactorial effect is the induction of GA-reactive T-cells in the periphery and their infiltration into the CNS, where they release immunomodulatory cytokines and neurotrophic factors in the injury site, suggesting a direct linkage to its therapeutic effect in both EAE and MS.

Aharoni R, Teitelbaum D, Sela M, Arnon R (1997) Copolymer 1 induces T cells of the T helper type 2 that cross react with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 94:10821–10826CrossRefPubMed

Aharoni R, Teitelbaum D, Leitner O, Meshorer A, Sela M, Arnon R (2000) Specific Th2 cells accumulate in the central nervous system of mice protected against EE by copolymer. PNAS USA 97:11472–11477CrossRefPubMed

Aharoni R, Kayhan B, Eilam R, Sela M, Arnon R (2003) Glatiramer acetate specific T-cells in the brain express TH2/3 cytokines and brain-derived neurotrophic factor in situ. PNAS 100(24):14157–14162CrossRefPubMed

Aharoni R, Eylam R, Domev H, Labunsky G, Sela M, Arnon R (2005a) The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. PNAS 102(52):19045–19050CrossRefPubMed

Aharoni R, Arnon R, Eilam R (2005b) Neurogenesis and neuroprotection induced by peripheral immunomodulatory treatment of experimental autoimmune encephalomyelitis. J Neuroscience 25(36):8217–8228CrossRef

Aharoni R, Herschkovitz A, Eilam R, Blumberg-Hazan M, Sela M, Bruck W, Arnon R (2008) Demyelination arrest and remyelination induced by glatiramer acetate treatment of experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 105(32):11358–11363CrossRefPubMed

Althau HH (2004) Remyelination in multiple sclerosis: a new role for neurotrophins? Prog Brain Res 146:415–432CrossRef

Angelov DN, Waibel S, Guntinas-Lichius O et al (2004) Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 101:15823–15828CrossRef

Arnon R (1996) The development of Cop 1 (Copaxone^®), an innovative drug for the treatment of multiple sclerosis: personal reflections. Immunol Lett 50:1–15CrossRefPubMed

Arnon R, Sela M (2003) Immunomodulation by the copolymer glatiramer acetate. J Mol Recognition 16:412–421CrossRef

Azoulay D, Vachapova V, Shihman B, Miler A, Karni A (2005) Lower brain-derived neurotrophic factor in serum of relapsing remitting MS: Reversal by glatiramer acetate. J Neuroimmunol 167:215–218CrossRefPubMed

Benner EJ, Mosley RI, Destache CJ et al (2004) Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 101:9435–9440CrossRefPubMed

Bitsch A, Schuchardt J, Bunkowski S (2000) Acute axonal injury in multiple sclerosis Correlation with demyelination and inflammation. Brain 123:1174–1183CrossRefPubMed

Bitsch A, Kuhlmann T, Stadelmann C, Lassmann H, Lucchinetti C, Brück W (2001) A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions. Ann Neurol 49:793–796CrossRefPubMed

Bjartmar C, Trapp BD (2001) Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol 14:271–278CrossRefPubMed

Bjartmar C, Wujek JR, Trapp BD (2003) Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci 15:165–171CrossRef

Brown JP, Couillard-Despres S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG (2003) Transient expression of double cortin during adult neurogenesis. J of Comparative Neurol 467:1–10CrossRef

Caggiula M, Batocchi AP, Frisullo G, Angelucci F, Patanella AK, Sancricca C, Nociti V, Tonali PA, Mirabella M (2005) Neurotrophic factors and clinical recovery in relapsing-remitting multiple sclerosis. Scand J Immunol 62:176–182CrossRefPubMed

Chen M, Valenzuela RM, Dhib-Jalbut S (2003) Glatiramer acetate-reactive T cells produce brain derived neurotrophic factor. J Neurol Sci 215:37–44CrossRefPubMed

Farina C, Weber MS, Meinl E, Wekerle H, Hohlfeld R (2005) Glatiramer acetate in multiple sclerosis: update on potential mechanisms of action. Neurol 4:567–575

Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, Nerbonne JM, Lichtman JW, Sanes JR (2000) Imaging neuronal subsets intransgenic mice expressing multiple spectral variants of GFP. Neuron 28:41–51CrossRefPubMed

Filippi M, Rovaris M, Rocca MA, the European/Canadian Glatiramer Acetate Study Group (2001) Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes”. Neurology 57:731–733PubMed

Ford CC, Johnson KP, Lisak RP, Panitch HS, Shifroni G, Wolinsky JS, the Copaxone Study Group (2006) A prospective open-labeled study of glatiramer acetate: over a decade of continuous use in multiple sclerosis patients. Mult Scler 12:309–320CrossRefPubMed

Franklin RJM, Hinks GL (1999) Understanding CNS remyelination: clues from developmental and regeneration biology. J Neurosci Res 58:207–213CrossRefPubMed

Fridkis-Hareli M, Teitelbaum D, Gurevich E, Pecht I, Brautbar C, Kwon OJ, Brenner T, Arnon R, Sela M (1994) Direct binding of myelin basic protein and synthetic copolymer 1 class II major histocompatibility complex molecules on living antigen presenting cells-specificity and promiscuity. Proc Natl Acad Sci USA 91:4872–4876CrossRefPubMed

Gilgun-Sherki Y, Panet H, Holdengreber V, Mosberg-Galili R, Offen D (2003) Axonal damage is reduced following glatiramer acetate treatment in C57/bl mice with chronic-induced experimental autoimmune encephalomyelitis. Neurosci Res 47:201–207CrossRefPubMed

Hellings N, Raus J, Stinissen P (2002) Insights into the immunopathogenesis of multiple sclerosis. Immunol Res 25:27–51CrossRefPubMed

Hobom M, Storch MK, Weissert R, Maier K, Radhakrishnan A, Kramer B, Bahr M, Diem R (2004) Mechanisms and time course of neuronal degeneration experimental autoimmune encephalomyelitis. Brain Pathol 14:148–157PubMed

Jin K, Sun Y, Xie L, Peel A, Mao XO, Batteur S, Greenberg DA (2003) Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci 24:171–189CrossRefPubMed

Johnson KP, Knobler RL, Greenstein JL et al (1990) Recombinant beta interferon treatment of relapsing-remitting multiple sclerosis pilot study results. Neurology 40(Suppl 1):261

Kawauchi S, Beites CL, Crocker CE, Wu HH, Bonnin A, Murray R, Calof AL (2004) Molecular signals regulating proliferation of stem and progenitor cells in mouse olfactory epithelium. Dev Neurosci 26:166–180CrossRefPubMed

Khan O, Shen Y, Caon C et al (2005) Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing-remitting multiple sclerosis. Mult Scler 11:646–651CrossRefPubMed

Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M, Cohen IR, Schwartz M (2000) T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. PNAS 97:7446–7451CrossRefPubMed

Kornek B, Lassmann H (1999) Axonal pathology in multiple sclerosis: a historical note. Brain Pathol 9:651–656PubMedCrossRef

Lalive PH, Paglinawan R, Biollaz G et al (2005) TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF-c-Met pathway. Eur J Immunol 35:727–737CrossRefPubMed

Lessman V, Gottmann K, Malcangio M (2003) Neurotrophin secretion: current facts and future prospect. Prog Neurobiol 69:341–374CrossRef

Magavi SS, Leavitt BR, Macklis JD (2000) Induction of neurogenesis in the neocortex of adult mice. Nature 405:951–955CrossRefPubMed

Murer MG, Yan O, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 63:71–124CrossRefPubMed

Neuhaus O, Farina C, Yassouridis A, Wiendl H, Then Bergh F, Dose T, Wekerle H, Hohlfeld R (2000) Multiple sclerosis comparison of copolymer-1 reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells. Proc Natl Acad Sci USA 97:7452–7457CrossRefPubMed

Picard-Riera N, Decker L, Delarasse C, Goude K, Nait-Oumesmar B, Liblau R, Pham-Dinh D, Evercooren AB (2002) Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. PNAS 99:13211–13216CrossRefPubMed

PRIM(Prevention of relapses, disability by Interferon beta-1a subsequently in multiple sclerosis) study group (1998) Randomized, double blind, placebo controlled study of Interferon beta-1a in relapsing-remitting multiple sclerosis: clinical results. Lancet 352:1498–1504CrossRef

Riley CP, Cope TC, Buck CR (2004) CNS neurotrophins are biologically active and expressed by multiple cell types. J Mol Histol 35:771–783CrossRefPubMed

Schori H, Kipnis J, Yoles E, WoldeMussie E, Ruiz G, Wheeler LA, Schwartz M (2001) Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implication for glaucoma. Proc Natl Acad Sci USA 98:3398–3403CrossRefPubMed

Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H (2002) BDNF and gp145 trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 125:75–85CrossRefPubMed

Van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in adult hippocampus. Nature 415:1000–1034CrossRef

Ziemssen T, Kumpfel T, Kinkert WEF, Neuhaus O, Hohlfeld R (2002) Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy brain-derived neurotrophic factor. Brain 125:2381–2391CrossRefPubMed

Title: Neuroprotection and neurogeneration in MS and its animal model EAE effected by glatiramer acetate
Authors: Ruth Arnon
Rina Aharoni
Publication date: 01-11-2009
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 11/2009
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-009-0272-3

At a glance: The STEP trials

Springer Medicine

Neuroprotection and neurogeneration in MS and its animal model EAE effected by glatiramer acetate

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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