Abstract
Multiple sclerosis (MS) is most frequently clinically characterized by an initial relapsing–remitting phase that evolves into a secondary progressive course; these phases can also be ongoing concurrently. Each of these clinical disease aspects reflects distinctive pathologic substrates, each of which may require its own therapeutic strategies. The pathologic correlate of clinical relapses is the development of new demyelinating lesions within the CNS that feature an inflammatory infiltrate comprised of cells of the adaptive (lymphocytes) and innate (myeloid cells) systems that have transgressed the blood–brain barrier (BBB) and/or the subarachnoid space/brain barrier (Kivisakk et al. 2003). Axonal transections are a further feature of the acute lesions (Trapp et al. 1998). Magnetic resonance imaging (MRI) studies indicate that multiple such lesions can occur without apparent clinical symptoms (Engell 1989). Recovery from relapses reflects the combined effects of multiple factors including resolution of inflammation, axonal adaptation to demyelination, remyelination, and cerebral reorganization. The pathologic correlates of the later progressive disease phase are even more complex involving changes both within initial lesions and in normal appearing white matter (NAWM) (Fu et al. 1998). Intralesional changes include further loss of oligodendrocytes (OLs) and axons, enhanced gliosis, and apparent failure of remyelination. Such lesions are dominated by innate immune cells (microglia/macrophages) rather than lymphocytes (Revesz et al. 1994). Observed changes in NAWM include continued decrease in axonal density and activated glial cells (microglia, astrocytes). There is also an apparent increase of lesions within the gray matter over time characterized by loss of neurons and demyelination without marked inflammation (Kidd et al. 1999). Ongoing remyelination is more apparent in recent rather than more chronic lesions and may be more prevalent in gray matter than in white matter lesions (Prineas and Connell 1979; Raine and Wu 1993; Stadelmann and Bruck 2008). Disease progression is thus likely to involve variable contributions by ongoing tissue injury, degeneration of previously injured OLs and neurons, and failure to initiate or sustain repair mechanisms (Table 9.1).
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References
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 experimental autoimmune encephalomyelitis by copolymer 1. Proc Natl Acad Sci USA 97:11472–11477
Aharoni R, Kayhan B, Eilam R, Sela M, Arnon R (2003) Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc Natl Acad Sci USA 100:14157–14162
Aharoni R, Arnon R, Eilam R (2005) Neurogenesis and neuroprotection induced by peripheral immunomodulatory treatment of experimental autoimmune encephalomyelitis. J Neurosci 25:8217–8228
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 105:11358–11363
Aharoni R, Vainshtein A, Stock A, Eilam R, From R, Shinder V, Arnon R (2011) Distinct pathological patterns in relapsing-remitting and chronic models of experimental autoimmune encephalomyelitis and the neuroprotective effect of glatiramer acetate. J Autoimmun 37(3):228–241
Aktas O, Schulze-Topphoff U, Zipp F (2007) The role of TRAIL/TRAIL receptors in central nervous system pathology. Front Biosci 12:2912–2921
Al-Izki S, Pryce G, Jackson SJ, Giovannoni G, Baker D (2011) Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Mult Scler 17(8):939–948
Althaus HH (2004) Remyelination in multiple sclerosis: a new role for neurotrophins? Prog Brain Res 146:415–432
Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122
Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM (2002) Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol 52:54–61
Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De SP, Naves R, Han M, Zhong F, Castellanos JG, Mair R, Christakos A, Kolkowitz I, Katz L, Killestein J, Polman CH, de Waal MR, Steinman L, Raman C (2010) T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 16:406–412
Balatoni B, Storch MK, Swoboda EM, Schonborn V, Koziel A, Lambrou GN, Hiestand PC, Weissert R, Foster CA (2007) FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res Bull 74:307–316
Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R (2010) Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology 74:1033–1040
Bar-Or A et al (2007) Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. Arch Neurol 64:1407–1415
Barouch R, Schwartz M (2002) Autoreactive T cells induce neurotrophin production by immune and neural cells in injured rat optic nerve: implications for protective autoimmunity. FASEB J 16:1304–1306
Bartosik-Psujek H, Belniak E, Mitosek-Szewczyk K, Dobosz B, Stelmasiak Z (2004) Interleukin-8 and RANTES levels in patients with relapsing-remitting multiple sclerosis (RR-MS) treated with cladribine. Acta Neurol Scand 109:390–392
Bechtold DA, Miller SJ, Dawson AC, Sun Y, Kapoor R, Berry D, Smith KJ (2006) Axonal protection achieved in a model of multiple sclerosis using lamotrigine. J Neurol 253:1542–1551
Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, Nemachek C, Green SR, Przedborski S, Gendelman HE (2004) Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 101:9435–9440
Bieber AJ, Warrington A, Asakura K, Ciric B, Kaveri SV, Pease LR, Rodriguez M (2002) Human antibodies accelerate the rate of remyelination following lysolecithin-induced demyelination in mice. Glia 37:241–249
Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, Gran B, Eaton J, Antel J, Frank JA, McFarland HF, Martin R (2000) Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 6:1167–1175
Biernacki K, Prat A, Blain M, Antel JP (2001) Regulation of Th1 and Th2 lymphocyte migration by human adult brain endothelial cells. J Neuropathol Exp Neurol 60:1127–1136
Biernacki K, Antel JP, Blain M, Narayanan S, Arnold DL, Prat A (2005) Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis. Arch Neurol 62:563–568
Billich A, Bornancin F, Devay P, Mechtcheriakova D, Urtz N, Baumruker T (2003) Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem 278:47408–47415
Bitsch A, Kuhlmann T, Stadelmann C, Lassmann H, Lucchinetti C, Bruck W (2001) A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions. Ann Neurol 49:793–796
Bornstein MB, Miller A, Slagle S, Weitzman M, Crystal H, Drexler E, Keilson M, Merriam A, Wassertheil-Smoller S, Spada V (1987) A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med 317:408–414
Bostock H, Sears TA (1976) Continuous conduction in demyelinated mammalian nerve fibers. Nature 263:786–787
Boutros T, Croze E, Yong VW (1997) Interferon-beta is a potent promoter of nerve growth factor production by astrocytes. J Neurochem 69:939–946
Bruck W, Wegner C (2011) Insight into the mechanism of laquinimod action. J Neurol Sci 306:173–179
Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW (2002) Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 125:1297–1308
Brunmark C, Runstrom A, Ohlsson L, Sparre B, Brodin T, Astrom M, Hedlund G (2002) The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J Neuroimmunol 130:163–172
Buttmann M (2010) Treating multiple sclerosis with monoclonal antibodies: a 2010 update. Expert Rev Neurother 10:791–809
Caggiula M, Batocchi AP, Frisullo G, Angelucci F, Patanella AK, Sancricca C, Nociti V, Tonali PA, Mirabella M (2006) Neurotrophic factors in relapsing remitting and secondary progressive multiple sclerosis patients during interferon beta therapy. Clin Immunol 118:77–82
Chari DM, Zhao C, Kotter MR, Blakemore WF, Franklin RJ (2006) Corticosteroids delay remyelination of experimental demyelination in the rodent central nervous system. J Neurosci Res 83:594–605
Chen J, Cui X, Zacharek A, Chopp M (2009) Increasing Ang1/Tie2 expression by simvastatin treatment induces vascular stabilization and neuroblast migration after stroke. J Cell Mol Med 13:1348–1357
Choi JW, Gardell SE, Herr DR, Rivera R, Lee C-W, Noguchi K, Teo ST, Tung YC, Lu M, Kennedy G, Chun J (2011) FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci USA 108:751–756
Chou YC, Lin SB, Tsai LH, Tsai HI, Lin CM (2003) Cholesterol deficiency increases the vulnerability of hippocampal glia in primary culture to glutamate-induced excitotoxicity. Neurochem Int 43:197–209
Claussen MC, Korn T (2012) Immune mechanisms of new therapeutic strategies in MS – teriflunomide. Clin Immunol 142(1):49–56
Coelho RP, Payne SG, Bittman R, Spiegel S, Sato-Bigbee C (2007) The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J Pharmacol Exp Ther 323:626–635
Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK (2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 359:1786–1801
Compston A, Coles A (2002) Multiple sclerosis. Lancet 359:1221–1231
Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj K, Sharrack B, Filippi M (2008) Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 371:2085–2092
Craner MJ, Damarjian TG, Liu S, Hains BC, Lo AC, Black JA, Newcombe J, Cuzner ML, Waxman SG (2005) Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia 49:220–229
Davis MD, Clemens JJ, Macdonald TL, Lynch KR (2005) Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem 280:9833–9841
Decker L, Ffrench-Constant C (2004) Lipid rafts and integrin activation regulate oligodendrocyte survival. J Neurosci 24:3816–3825
Du S, Sandoval F, Trinh P, Voskuhl RR (2010) Additive effects of combination treatment with Âanti-inflammatory and neuroprotective agents in experimental autoimmune encephalomyelitis. J Neuroimmunol 219:64–74
Edwards PA, Ericsson J (1999) Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway. Annu Rev Biochem 68:157–185
Elewa HF, Hilali H, Hess DC, Machado LS, Fagan SC (2006) Minocycline for short-term neuroprotection. Pharmacotherapy 26:515–521
Engell T (1989) A clinical patho-anatomical study of clinically silent multiple sclerosis. Acta Neurol Scand 79:428–430
Foster CA, Howard LM, Schweitzer A, Persohn E, Hiestand PC, Balatoni B, Reuschel R, Beerli C, Schwartz M, Billich A (2007) Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J Pharmacol Exp Ther 323:469–475
Foster CA, Mechtcheriakova D, Storch MK, Balatoni B, Howard LM, Bornancin F, Wlachos A, Sobanov J, Kinnunen A, Baumruker T (2009) FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain Pathol 19:254–266
Fox C, Dingman A, Derugin N, Wendland MF, Manabat C, Ji S, Ferriero DM, Vexler ZS (2005) Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab 25:1138–1149
Freedman MS (2007) Bone marrow transplantation: does it stop MS progression? J Neurol Sci 259:85–89
Fu L, Matthews PM, De SN, Worsley KJ, Narayanan S, Francis GS, Antel JP, Wolfson C, Arnold DL (1998) Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain 121(Pt 1):103–113
Fujino M, Funeshima N, Kitazawa Y, Kimura H, Amemiya H, Suzuki S, Li XK (2003) Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 305:70–77
Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg SP, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ (2010) A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 362:416–426
Glezer I, Lapointe A, Rivest S (2006) Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries. FASEB J 20:750–752
Goetzl EJ, Rosen H (2004) Regulation of immunity by lysosphingolipids and their G protein-coupled receptors. J Clin Invest 114:1531–1537
Gomez-Gallego M, Meca-Lallana J, Fernandez-Barreiro A (2008) Multiple sclerosis onset during etanercept treatment. Eur Neurol 59:91–93
Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6:1045–1053
Greenwood J, Steinman L, Zamvil SS (2006) Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 6:358–370
Greil R, Anether G, Johrer K, Tinhofer I (2003) Tracking death dealing by Fas and TRAIL in lymphatic neoplastic disorders: pathways, targets, and therapeutic tools. J Leukoc Biol 74:311–330
Gronseth GS, Ashman EJ (2000) Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54:1720–1725
Gurevich M, Gritzman T, Orbach R, Tuller T, Feldman A, Achiron A (2010) Laquinimod suppress antigen presentation in relapsing-remitting multiple sclerosis: in-vitro high-throughput gene expression study. J Neuroimmunol 221:87–94
Hasegawa Y, Suzuki H, Sozen T, Rolland W, Zhang JH (2010) Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke 41:368–374
Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358:676–688
Hempstead BL, Salzer JL (2002) Neurobiology. A glial spin on neurotrophins. Science 298:1184–1186
Hendrix S, Nitsch R (2007) The role of T helper cells in neuroprotection and regeneration. J Neuroimmunol 184:100–112
Hirsch M, Knight J, Tobita M, Soltys J, Panitch H, Mao-Draayer Y (2009) The effect of interferon-beta on mouse neural progenitor cell survival and differentiation. Biochem Biophys Res Commun 388:181–186
Hohlfeld R, Barkhof F, Polman C (2011) Future clinical challenges in multiple sclerosis: relevance to sphingosine 1-phosphate receptor modulator therapy. Neurology 76:S28–S37
Holmberg E, Nordstrom T, Gross M, Kluge B, Zhang SX, Doolen S (2006) Simvastatin promotes neurite outgrowth in the presence of inhibitory molecules found in central nervous system injury. J Neurotrauma 23:1366–1378
Hoxtermann S, Nuchel C, Altmeyer P (1998) Fumaric acid esters suppress peripheral CD4- and CD8-positive lymphocytes in psoriasis. Dermatology 196:223–230
Hu Y, Lee X, Ji B, Guckian K, Apicco D, Pepinsky RB, Miller RH, Mi S (2011) Sphingosine 1-phosphate receptor modulator fingolimod (FTY720) does not promote remyelination in vivo. Mol Cell Neurosci 48:72–81
Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH (1995) A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating-remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients. Multiple Sclerosis Collaborative Research Group (MSCRG). Mult Scler 1:118–135
Jaillard C, Harrison S, Stankoff B, Aigrot MS, Calver AR, Duddy G, Walsh FS, Pangalos MN, Arimura N, Kaibuchi K, Zalc B, Lubetzki C (2005) Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci 25:1459–1469
Javed A, Reder AT (2006) Therapeutic role of beta-interferons in multiple sclerosis. Pharmacol Ther 110:35–56
Jung CG, Kim HJ, Miron VE, Cook S, Kennedy TE, Foster CA, Antel JP, Soliven B (2007) Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia 55:1656–1667
Jurevics H, Morell P (1995) Cholesterol for synthesis of myelin is made locally, not imported into brain. J Neurochem 64:895–901
Kalkers NF, Barkhof F, Bergers E, van Schijndel R, Polman CH (2002) The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult Scler 8:532–533
Kappos L, Traboulsee A, Constantinescu C, Eralinna JP, Forrestal F, Jongen P, Pollard J, Sandberg-Wollheim M, Sindic C, Stubinski B, Uitdehaag B, Li D (2006a) Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology 67:944–953
Kappos L, Antel J, Comi G, Montalban X, O’Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW (2006b) Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 355:1124–1140
Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O’Neill GN (2008) Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 372:1463–1472
Kataoka H, Sugahara K, Shimano K, Teshima K, Koyama M, Fukunari A, Chiba K (2005) FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol Immunol 2:439–448
Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE, Kolbeck R, Hoppe E, Oropeza-Wekerle RL, Bartke I, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R (1999) Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189:865–870
Keszthelyi E, Karlik S, Hyduk S, Rice GP, Gordon G, Yednock T, Horner H (1996) Evidence for a prolonged role of alpha 4 integrin throughout active experimental allergic encephalomyelitis. Neurology 47:1053–1059
Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L, Montalban X, Pelletier J, Stites T, Wu S, Holdbrook F, Zhang-Auberson L, Francis G, Cohen JA (2011) Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 10:520–529
Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T (1999) Cortical lesions in multiple sclerosis. Brain 122(Pt 1):17–26
Kim HJ, Ifergan I, Antel JP, Seguin R, Duddy M, Lapierre Y, Jalili F, Bar-Or A (2004) Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J Immunol 172:7144–7153
Kim HJ, Miron VE, Dukala D, Proia RL, Ludwin SK, Traka M, Antel JP, Soliven B (2011) Neurobiological effects of sphingosine 1-phosphate receptor modulation in the cuprizone model. FASEB J 25:1509–1518
Kipnis J, Schwartz M (2002) Dual action of glatiramer acetate (Cop-1) in the treatment of CNS autoimmune and neurodegenerative disorders. Trends Mol Med 8:319–323
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. Proc Natl Acad Sci USA 97:7446–7451
Kivisakk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, Wu L, Baekkevold ES, Lassmann H, Staugaitis SM, Campbell JJ, Ransohoff RM (2003) Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci USA 100:8389–8394
Klopfleisch S, Merkler D, Schmitz M, Kloppner S, Schedensack M, Jeserich G, Althaus HH, Bruck W (2008) Negative impact of statins on oligodendrocytes and myelin formation in vitro and in vivo. J Neurosci 28:13609–13614
Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332
Kumano T, Mutoh T, Nakagawa H, Kuriyama M (2000) HMG-CoA reductase inhibitor induces a transient activation of high affinity nerve growth factor receptor, trk, and morphological differentiation with fatal outcome in PC12 cells. Brain Res 859:169–172
Lee SM, Yune TY, Kim SJ, Park DW, Lee YK, Kim YC, Oh YJ, Markelonis GJ, Oh TH (2003) Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma 20:1017–1027
Lin CI, Chen CN, Lin PW, Chang KJ, Hsieh FJ, Lee H (2007) Lysophosphatidic acid regulates inflammation-related genes in human endothelial cells through LPA1 and LPA3. Biochem Biophys Res Commun 363:1001–1008
Lin W, Kunkler PE, Harding HP, Ron D, Kraig RP, Popko B (2008) Enhanced integrated stress response promotes myelinating oligodendrocyte survival in response to interferon-gamma. Am J Pathol 173:1508–1517
Lindberg C, Crisby M, Winblad B, Schultzberg M (2005) Effects of statins on microglia. J Neurosci Res 82:10–19
Linker RA, Lee DH, Demir S, Wiese S, Kruse N, Siglienti I, Gerhardt E, Neumann H, Sendtner M, Luhder F, Gold R (2010) Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis. Brain 133:2248–2263
Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Bruck W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678–692
Liu CH, Thangada S, Lee MJ, Van Brocklyn JR, Spiegel S, Hla T (1999) Ligand-induced trafficking of the sphingosine-1-phosphate receptor EDG-1. Mol Biol Cell 10:1179–1190
Liu J, Johnson TV, Lin J, Ramirez SH, Bronich TK, Caplan S, Persidsky Y, Gendelman HE, Kipnis J (2007) T cell independent mechanism for copolymer-1-induced neuroprotection. Eur J Immunol 37:3143–3154
Luger TA, Bhardwaj RS, Grabbe S, Schwarz T (1996) Regulation of the immune response by epidermal cytokines and neurohormones. J Dermatol Sci 13:5–10
Lum M, Croze E, Wagner C, McLenachan S, Mitrovic B, Turnley AM (2009) Inhibition of neurosphere proliferation by IFNgamma but not IFNbeta is coupled to neuronal differentiation. J Neuroimmunol 206:32–38
Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296:346–349
Maysami S, Nguyen D, Zobel F, Pitz C, Heine S, Hopfner M, Stangel M (2006) Modulation of rat oligodendrocyte precursor cells by the chemokine CXCL12. Neuroreport 17:1187–1190
Menge T, Hartung HP, Stuve O (2005) Statins – a cure-all for the brain? Nat Rev Neurosci 6:325–331
Mews I, Bergmann M, Bunkowski S, Gullotta F, Bruck W (1998) Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Mult Scler 4:55–62
Michikawa M, Yanagisawa K (1999) Inhibition of cholesterol production but not of nonsterol isoprenoid products induces neuronal cell death. J Neurochem 72:2278–2285
Miller AA, Wheatley P, Sawyer DA, Baxter MG, Roth B (1986) Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: I. Anticonvulsant profile in mice and rats. Epilepsia 27:483–489
Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O’Connor PW (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348:15–23
Miller A, Spada V, Beerkircher D, Kreitman RR (2008) Long-term (up to 22 years), open-label, compassionate-use study of glatiramer acetate in relapsing-remitting multiple sclerosis. Mult Scler 14:494–499
Miron VE, Rajasekharan S, Jarjour AA, Zamvil SS, Kennedy TE, Antel JP (2007) Simvastatin regulates oligodendroglial process dynamics and survival. Glia 55:130–143
Miron VE, Hall JA, Kennedy TE, Soliven B, Antel JP (2008a) Cyclical and dose-dependent responses of adult human mature oligodendrocytes to fingolimod. Am J Pathol 173:1143–1152
Miron VE, Jung CG, Kim HJ, Kennedy TE, Soliven B, Antel JP (2008b) FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol 63:61–71
Miron VE, Zehntner SP, Kuhlmann T, Ludwin SK, Owens T, Kennedy TE, Bedell BJ, Antel JP (2009) Statin therapy inhibits remyelination in the central nervous system. Am J Pathol 174:1880–1890
Miron VE, Ludwin SK, Darlington PJ, Jarjour AA, Soliven B, Kennedy TE, Antel JP (2010) Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am J Pathol 176:2682–2694
Moharregh-Khiabani D, Blank A, Skripuletz T, Miller E, Kotsiari A, Gudi V, Stangel M (2010) Effects of fumaric acids on cuprizone induced central nervous system de- and remyelination in the mouse. PLoS One 5:e11769
Morell P, Jurevics H (1996) Origin of cholesterol in myelin. Neurochem Res 21:463–470
Mullershausen F, Craveiro LM, Shin Y, Cortes-Cros M, Bassilana F, Osinde M, Wishart WL, Guerini D, Thallmair M, Schwab ME, Sivasankaran R, Seuwen K, Dev KK (2007) Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem 102:1151–1161
Narayanan S, De SN, Francis GS, Arnaoutelis R, Caramanos Z, Collins DL, Pelletier D, Arnason BGW, Antel JP, Arnold DL (2001) Axonal metabolic recovery in multiple sclerosis patients treated with interferon beta-1b. J Neurol 248:979–986
Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID (2007) Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/betaII. J Biol Chem 282:15208–15216
Nikodemova M, Lee J, Fabry Z, Duncan ID (2010) Minocycline attenuates experimental autoimmune encephalomyelitis in rats by reducing T cell infiltration into the spinal cord. J Neuroimmunol 219:33–37
Novgorodov AS, El Alwani M, Bielawski J, Obeid LM, Gudz TI (2007) Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J 21:1503–1514
Nuesslein-Hildesheim B, Zecri FJ, Bruns C, Cooke N, Seabrook T, Smith PA (2010) BAF312, a potent and selective S1P1/5 receptor modulator reverses ongoing chronic EAE in mice. In: American Academy of Neurology 62nd Annual Meeting, Toronto, Canada
O’Connor PW, Goodman A, Willmer-Hulme AJ, Libonati MA, Metz L, Murray RS, Sheremata WA, Vollmer TL, Stone LA (2004) Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. Neurology 62:2038–2043
Osinde M, Mullershausen F, Dev KK (2007) Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors. Neuropharmacology 52:1210–1218
Oyama Y, Chikahisa L, Kanemaru K, Nakata M, Noguchi S, Nagano T, Okazaki E, Hirata A (1998) Cytotoxic actions of FTY720, a novel immunosuppressant, on thymocytes and brain neurons dissociated from the rat. Jpn J Pharmacol 76:377–385
Pahan K, Sheikh FG, Namboodiri AM, Singh I (1997) Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest 100:2671–2679
Paintlia AS, Paintlia MK, Singh AK, Stanislaus R, Gilg AG, Barbosa E, Singh I (2004) Regulation of gene expression associated with acute experimental autoimmune encephalomyelitis by Lovastatin. J Neurosci Res 77:63–81
Paintlia AS, Paintlia MK, Khan M, Vollmer T, Singh AK, Singh I (2005) HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. FASEB J 19:1407–1421
Panitch HS, Hirsch RL, Schindler J, Johnson KP (1987) Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 37:1097–1102
Peng X, Jin J, Giri S, Montes M, Sujkowski D, Tang Y, Smrtka J, Vollmer T, Singh I, Markovic-Plese S (2006) Immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, potential therapy for relapsing remitting multiple sclerosis. J Neuroimmunol 178:130–139
Phadke JG, Best PV (1983) Atypical and clinically silent multiple sclerosis: a report of 12 cases discovered unexpectedly at necropsy. J Neurol Neurosurg Psychiatry 46:414–420
Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID (2002) Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 51:215–223
Prineas JW, Connell F (1979) Remyelination in multiple sclerosis. Ann Neurol 5:22–31
Raine CS, Wu E (1993) Multiple sclerosis: remyelination in acute lesions. J Neuropathol Exp Neurol 52:199–204
Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI (1994) A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain 117(Pt 4):759–765
Riley CP, Cope TC, Buck CR (2004) CNS neurotrophins are biologically active and expressed by multiple cell types. J Mol Histol 35:771–783
Rodriguez M, Zoecklein LJ, Howe CL, Pavelko KD, Gamez JD, Nakane S, Papke LM (2003) Gamma interferon is critical for neuronal viral clearance and protection in a susceptible mouse strain following early intracranial Theiler’s murine encephalomyelitis virus infection. J Virol 77:12252–12265
Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG (2007) Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results. Neurology 69:785–789
Runstrom A, Leanderson T, Ohlsson L, Axelsson B (2006) Inhibition of the development of chronic experimental autoimmune encephalomyelitis by laquinimod (ABR-215062) in IFN-beta k.o. and wild type mice. J Neuroimmunol 173:69–78
Saganova K, Orendacova J, Cizkova D, Vanicky I (2008) Limited minocycline neuroprotection after balloon-compression spinal cord injury in the rat. Neurosci Lett 433:246–249
Saheki A, Terasaki T, Tamai I, Tsuji A (1994) In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Pharm Res 11:305–311
Saher G, Brugger B, Lappe-Siefke C, Mobius W, Tozawa R, Wehr MC, Wieland F, Ishibashi S, Nave KA (2005) High cholesterol level is essential for myelin membrane growth. Nat Neurosci 8:468–475
Sanchez T, Hla T (2004) Structural and functional characteristics of S1P receptors. J Cell Biochem 92:913–922
Sawicka E, Dubois G, Jarai G, Edwards M, Thomas M, Nicholls A, Albert R, Newson C, Brinkmann V, Walker C (2005) The sphingosine 1-phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/CD25+ T-regulatory cells and enhances their functional activity. J Immunol 175:7973–7980
Schori H, Yoles E, Schwartz M (2001) T-cell-based immunity counteracts the potential toxicity of glutamate in the central nervous system. J Neuroimmunol 119:199–204
Shapiro AM, Jack CS, Lapierre Y, Arbour N, Bar-Or A, Antel JP (2006) Potential for interferon beta-induced serum antibodies in multiple sclerosis to inhibit endogenous interferon-regulated chemokine/cytokine responses within the central nervous system. Arch Neurol 63:1296–1299
Skihar V, Silva C, Chojnacki A, Doring A, Stallcup WB, Weiss S, Yong VW (2009) Promoting oligodendrogenesis and myelin repair using the multiple sclerosis medication glatiramer acetate. Proc Natl Acad Sci USA 106:17992–17997
Smith KJ, Felts PA, John GR (2000) Effects of 4-aminopyridine on demyelinated axons, synapses and muscle tension. Brain 123(Pt 1):171–184
Stadelmann C, Bruck W (2008) Interplay between mechanisms of damage and repair in multiple sclerosis. J Neurol 255(Suppl 1):12–18
Tarhzaoui K, Valensi P, Leger G, Cohen-Boulakia F, Lestrade R, Behar A (2009) Rosuvastatin positively changes nerve electrophysiology in diabetic rats. Diabetes Metab Res Rev 25:272–278
Tham CS, Lin FF, Rao TS, Yu N, Webb M (2003) Microglial activation state and lysophospholipid acid receptor expression. Int J Dev Neurosci 21:431–443
Thone J, Gold R (2011) Laquinimod: a promising oral medication for the treatment of relapsing-remitting multiple sclerosis. Expert Opin Drug Metab Toxicol 7:365–370
Toman RE, Payne SG, Watterson KR, Maceyka M, Lee NH, Milstien S, Bigbee JW, Spiegel S (2004) Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension. J Cell Biol 166:381–392
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285
Tringali G, Vairano M, Dello RC, Preziosi P, Navarra P (2004) Lovastatin and mevastatin reduce basal and cytokine-stimulated production of prostaglandins from rat microglial cells in vitro: evidence for a mechanism unrelated to the inhibition of hydroxy-methyl-glutaryl CoA reductase. Neurosci Lett 354:107–110
van HJ, Drexhage JA, Flor T, Gerritsen W, van der Valk P, de Vries HE (2010) Nrf2 and DJ1 are consistently upregulated in inflammatory multiple sclerosis lesions. Free Radic Biol Med 49:1283–1289
van Oosten BW, Barkhof F, Truyen L, Boringa JB, Bertelsmann FW, von Blomberg BM, Woody JN, Hartung HP, Polman CH (1996) Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47:1531–1534
Vela JM, Yanez A, Gonzalez B, Castellano B (2002) Time course of proliferation and elimination of microglia/macrophages in different neurodegenerative conditions. J Neurotrauma 19: 1503–1520
Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, Preiningerova J, Rizzo M, Singh I (2004) Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 363:1607–1608
Wandinger KP, Lunemann JD, Wengert O, Bellmann-Strobl J, Aktas O, Weber A, Grundstrom E, Ehrlich S, Wernecke KD, Volk HD, Zipp F (2003) TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet 361:2036–2043
Wang Q, Yan J, Chen X, Li J, Yang Y, Weng J, Deng C, Yenari MA (2011) Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol 230(1):27–34
Webb M, Tham CS, Lin FF, Lariosa-Willingham K, Yu N, Hale J, Mandala S, Chun J, Rao TS (2004) Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 153:108–121
Wegner C, Stadelmann C, Pfortner R, Raymond E, Feigelson S, Alon R, Timan B, Hayardeny L, Bruck W (2010) Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 227:133–143
Wierinckx A, Breve J, Mercier D, Schultzberg M, Drukarch B, van Dam AM (2005) Detoxication enzyme inducers modify cytokine production in rat mixed glial cells. J Neuroimmunol 166:132–143
Wosik K, Antel J, Kuhlmann T, Bruck W, Massie B, Nalbantoglu J (2003) Oligodendrocyte injury in multiple sclerosis: a role for p53. J Neurochem 85:635–644
Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771
Xue M, Mikliaeva EI, Casha S, Zygun D, Demchuk A, Yong VW (2010) Improving outcomes of neuroprotection by minocycline: guides from cell culture and intracerebral hemorrhage in mice. Am J Pathol 176:1193–1202
Yang JS, Xu LY, Xiao BG, Hedlund G, Link H (2004) Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J Neuroimmunol 156:3–9
Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 356:63–66
Yoshimura S, Ochi H, Isobe N, Matsushita T, Motomura K, Matsuoka T, Minohara M, Kira J (2010) Altered production of brain-derived neurotrophic factor by peripheral blood immune cells in multiple sclerosis. Mult Scler 16:1178–1788
Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420:78–84
Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 95:15769–15774
Yu N, Lariosa-Willingham KD, Lin FF, Webb M, Rao TS (2004) Characterization of lysophosphatidic acid and sphingosine-1-phosphate-mediated signal transduction in rat cortical oligodendrocytes. Glia 45:17–27
Zanon RG, Cartarozzi LP, Victório SCS, Moraes JC, Morari J, Velloso LA, Oliveira ALR (2010) Interferon (IFN) beta treatment induces major histocompatibility complex (MHC) class I expression in the spinal cord and enhances axonal growth and motor function recovery following sciatic nerve crush in mice. Neuropathol Appl Neurobiol 36:515–534
Zarkou S, Carter JL, Wellik KE, Demaerschalk BM, Wingerchuk DM (2010) Are corticosteroids efficacious for preventing or treating neutralizing antibodies in multiple sclerosis patients treated with beta-interferons? A critically appraised topic. Neurologist 16:212–214
Zemann B, Kinzel B, Muller M, Reuschel R, Mechtcheriakova D, Urtz N, Bornancin F, Baumruker T, Billich A (2006) Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. Blood 107:1454–1458
Zhang SC, Goetz BD, Duncan ID (2003) Suppression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors. Glia 41:191–198
Zhang Y, Taveggia C, Melendez-Vasquez C, Einheber S, Raine CS, Salzer JL, Brosnan CF, John GR (2006) Interleukin-11 potentiates oligodendrocyte survival and maturation, and myelin formation. J Neurosci 26:12174–12185
Zhang Z, Zhang Z, Fauser U, Artelt M, Burnet M, Schluesener HJ (2007) FTY720 attenuates accumulation of EMAP-II+ and MHC-II+ monocytes in early lesions of rat traumatic brain injury. J Cell Mol Med 11:307–314
Zhang Y, Metz LM, Yong VW, Bell RB, Yeung M, Patry DG, Mitchell JR (2008) Pilot study of minocycline in relapsing-remitting multiple sclerosis. Can J Neurol Sci 35:185–191
Zhang J, Zhang A, Sun Y, Cao X, Zhang N (2009) Treatment with immunosuppressants FTY720 and tacrolimus promotes functional recovery after spinal cord injury in rats. Tohoku J Exp Med 219:295–302
Zhang Y, Jalili F, Ouamara N, Zameer A, Cosentino G, Mayne M, Hayardeny L, Antel JP, Bar-Or A, John GR (2010) Glatiramer acetate-reactive T lymphocytes regulate oligodendrocyte progenitor cell number in vitro: role of IGF-2. J Neuroimmunol 227:71–79
Ziemssen T, Kumpfel T, Klinkert WE, 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 125:2381–2391
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Antel, J.P., Miron, V.E. (2013). Effects of Current Medical Therapies on Reparative and Neuroprotective Functions in Multiple Sclerosis. In: Duncan, I., Franklin, R. (eds) Myelin Repair and Neuroprotection in Multiple Sclerosis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-2218-1_9
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