Seminars in Immunopathology

, Volume 31, Issue 4, pp 455–465 | Cite as

Progressive multiple sclerosis

Review
First Online:
Received:
Accepted:

Abstract

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system, which starts in the majority of patients with a relapsing/remitting MS (RRMS) course , which after several years of disease duration converts into a progressive disease. Since anti-inflammatory therapies and immune modulation exert a beneficial effect at the relapsing/remitting stage of the disease, but not in the progressive stage, the question was raised whether inflammation drives tissue damage in progressive MS at all. We show here that also in progressive MS, inflammation is the driving force for brain injury and that the discrepancy between inflammation-driven tissue injury and response to immunomodulatory therapies can be explained by different pathomechanisms acting in RRMS and progressive MS.

Keywords

Multiple sclerosis Inflammation Microglia Neurodegeneration Mitochondria Age Progressive MS Relapsing/remitting MS 
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References

  1. 1.
    Charcot JM (1880) Lecons sur les maladies du systeme nerveux faites a la Salpetriere. V. Adrien Delahaye et Cie, ParisGoogle Scholar
  2. 2.
    Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46:907–911PubMedGoogle Scholar
  3. 3.
    Cotton F, Weiner HL, Jolesz FA, Guttmann CR (2003) MRI contrast uptake in new lesions in relapsing/remitting MS followed at weekly intervals. Neurology 60:640–646. doi: 10.1001/archneur.60.4.640-a PubMedCrossRefGoogle Scholar
  4. 4.
    Katz D, Taubenberger JK, Cannella B, McFarlin DE, Raine CS, McFarland HF (1993) Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol 34:661–669. doi: 10.1002/ana.410340507 PubMedCrossRefGoogle Scholar
  5. 5.
    Coles AJ, Wing MG, Molyneux P, Paolillo A, Davie CM, Hale G, Miller D, Waldmann H, Compston A (1999) Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 46:296–304. doi: 10.1002/1531-8249(199909)46:3<296::AID-ANA4>3.0.CO;2-# PubMedCrossRefGoogle Scholar
  6. 6.
    Anderson VM, Fox NC, Miller DH (2006) Magnetic resonance imaging measures of brain atrophy in multiple sclerosis. J Magn Reson Imaging 23:605–618. doi: 10.1002/jmri.20550 PubMedCrossRefGoogle Scholar
  7. 7.
    Bielekova B, Kadom N, Fisher E, Jeffries N, Ohayon J, Richert N, Howard T, Bash CN, Frank JA, Stone L, Martin R, Cutter G, McFarland HF (2005) MRI as a marker for disease heterogeneity in multiple sclerosis. Neurology 65:1071–1076. doi: 10.1212/01.wnl.0000178984.30534.f9 PubMedCrossRefGoogle Scholar
  8. 8.
    Zivadinov R, Cox JL (2007) Neuroimaging in multiple sclerosis. Int Rev Neurobiol 79:449–474. doi: 10.1016/S0074-7742(07)79020-7 PubMedCrossRefGoogle Scholar
  9. 9.
    Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269. doi: 10.1146/annurev.neuro.30.051606.094313 PubMedCrossRefGoogle Scholar
  10. 10.
    Lassmann H, Brück W, Lucchinetti CF (2007) The immunopathology of multiple sclerosis: an overview. Brain Pathol 17:210–218. doi: 10.1111/j.1750-3639.2007.00064.x PubMedCrossRefGoogle Scholar
  11. 11.
    Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400. doi: 10.1002/ana.1123 PubMedCrossRefGoogle Scholar
  12. 12.
    Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712. doi: 10.1093/brain/awh641 PubMedCrossRefGoogle Scholar
  13. 13.
    Kutzelnigg A, Faber-Rod JC, Bauer J, Lucchinetti CF, Sorensen PS, Laursen H, Stadelmann C, Brück W, Rauschka H, Schmidbauer M, Lassmann H (2007) Widespread demyelination in the cerebellar cortex in multiple sclerosis. Brain Pathol 17:38–44. doi: 10.1111/j.1750-3639.2006.00041.x PubMedCrossRefGoogle Scholar
  14. 14.
    Geurts JJ, Bo L, Roosendaal SD, Hazes T, Daniels R, Barkhof F, Witter MP, Huitinga I, van der Valk P (2007) Extensive hippocampal demyelination in multiple sclerosis. J Neuropathol Exp Neurol 66:819–827. doi: 10.1097/nen.0b013e3181461f54 PubMedCrossRefGoogle Scholar
  15. 15.
    Jellinger K (1969) Einige morphologische Aspekte der Multiplen Sklerose. Wien Z Nervenheilk (Suppl. II):12–37Google Scholar
  16. 16.
    Lovas G, Szilagyi N, Majtenyi K, Palkovits M, Komoly S (2000) Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 123:308–317. doi: 10.1093/brain/123.2.308 PubMedCrossRefGoogle Scholar
  17. 17.
    Evangelou N, DeLuca GC, Owens T, Esiri MM (2005) Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions. Brain 128:29–34. doi: 10.1093/brain/awh323 PubMedCrossRefGoogle Scholar
  18. 18.
    DeLuca GC, Williams K, Evangelou N, Ebers GC, Esiri MM (2006) The contribution of demyelination to axonal loss in multiple sclerosis. Brain 129:1507–1516. doi: 10.1093/brain/awl074 PubMedCrossRefGoogle Scholar
  19. 19.
    Bergers E, Bot JC, De Groot CJ, Polman CH, Lycklama à Nijeholt GJ, Castelijns JA, van der Valk P, Barkhof F (2002) Axonal damage in the spinal cord of MS patients occurs largely independent of T2 MRI lesions. Neurology 59:1766–1771PubMedGoogle Scholar
  20. 20.
    Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H (2009) The relation between inflammation and neurodegeneration in multiple sclerosis. Brain 132(Pt. 5):1175–1189PubMedCrossRefGoogle Scholar
  21. 21.
    Lassmann H (2008) The pathologic substrate of magnetic resonance alterations in multiple sclerosis. Neuroimaging Clin N Am 18:563–576. doi: 10.1016/j.nic.2008.06.005 PubMedCrossRefGoogle Scholar
  22. 22.
    Hochmeister S, Grundtner R, Bauer J, Engelhardt B, Lyck R, Gordon G, Korosec T, Kutzelnigg A, Berger J, Bradl M, Bittner RE, Lassmann H (2006) Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J Neuropathol Exp Neurol 65:855–865. doi: 10.1097/01.jnen.0000235119.52311.16 PubMedCrossRefGoogle Scholar
  23. 23.
    Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F (2004) Detection of ectopic B cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14:164–174PubMedCrossRefGoogle Scholar
  24. 24.
    Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, Reynolds R, Aloisi F (2007) Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130:1089–1104. doi: 10.1093/brain/awm038 PubMedCrossRefGoogle Scholar
  25. 25.
    Aloisi F, Pujol-Borrell R (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6:205–217. doi: 10.1038/nri1786 PubMedCrossRefGoogle Scholar
  26. 26.
    Randall TD, Carragher DM, Rangel-Moreno J (2008) Development of secondary lymphoid organs. Annu Rev Immunol 26:627–650. doi: 10.1146/annurev.immunol.26.021607.090257 PubMedCrossRefGoogle Scholar
  27. 27.
    Luther SA, Bidgol A, Hargreaves DC, Schmidt A, Xu Y, Paniyadi J, Matloubian M, Cyster JG (2002) Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol 169:424–433PubMedGoogle Scholar
  28. 28.
    Luther SA, Lopez T, Bai W, Hanahan D, Cyster JG (2009) BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 12:471–481. doi: 10.1016/S1074-7613(00)80199-5 CrossRefGoogle Scholar
  29. 29.
    Fan L, Reilly CR, Luo Y, Dorf ME, Lo D (2000) Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J Immunol 164:3955–3959PubMedGoogle Scholar
  30. 30.
    Lindhout E, van Eijk M, van Pel M, Lindeman J, Dinant HJ, De Groot CJ (1999) Fibroblast-like synoviocytes from rheumatoid arthritis patients have intrinsic properties of follicular dendritic cells. J Immunol 162:5949–5956PubMedGoogle Scholar
  31. 31.
    Parsonage G, Filer AD, Haworth O, Nash GB, Rainger GE, Salmon M, Buckley CD (2005) A stromal address code defined by fibroblasts. Trends Immunol 26:150–156. doi: 10.1016/j.it.2004.11.014 PubMedCrossRefGoogle Scholar
  32. 32.
    Park CS, Choi YS (2009) How do follicular dendritic cells interact intimately with B cells in the germinal centre? Immunology 114:2–10. doi: 10.1111/j.1365-2567.2004.02075.x CrossRefGoogle Scholar
  33. 33.
    Gräbner R, Lötzer K, Döpping S, Hildner M, Radke D, Beer M, Spanbroek R, Lippert B, Reardon CA, Getz GS, Fu Y-X, Hehlgans T, Mebius RE, van der Wall M, Kruspe D, Englert C, Lovas A, Hu D, Randolph GJ, Weih F, Habenicht AJR (2009) Lymphotoxin b receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med 206:233–248. doi: 10.1084/jem.20080752 PubMedCrossRefGoogle Scholar
  34. 34.
    Roozendaal R, Mempel TR, Pitcher LA, Gonzales SF, Verschoor A, Mebius RE, von Adrian UH, Carroll MC (2009) Conduits mediate transport of low molecular weight antigen to lymph node follicles. Immunity 30:264–276. doi: 10.1016/j.immuni.2008.12.014 PubMedCrossRefGoogle Scholar
  35. 35.
    Roozendaal R, Mebius RE, Kraal G (2008) The conduit system of the lymph node. Int Immunol. doi: 10.1093/intimm/dxn110 PubMedGoogle Scholar
  36. 36.
    Kuscher K, Danelon G, Paoletti S, Stefano L, Schiraldi M, Petkovic V, Locati M, Gerber BO, Uguccioni M (2009) Synergy-inducing chemokines enhance CCR2 ligand activities on monocytes. Eur J Immunol 39:1–11. doi: 10.1002/eji.200838906 CrossRefGoogle Scholar
  37. 37.
    Kokaji AI, Hockley DL, Kane KP (2008) IL-15 transpresentation augments CD8+ T cell activation and is required for optimal recall responses by central memory CD8+ T cells. J Immunol 180:4391–4401PubMedGoogle Scholar
  38. 38.
    Kivisakk P, Mahad D, Callahan MK, Sikora K, Trebst C, Tucky B, Wujek J, Ravid R, Staugaitis SM, Lassmann H, Ransohoff RM (2004) Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol 55:627–638. doi: 10.1002/ana.20049 PubMedCrossRefGoogle Scholar
  39. 39.
    Chikuma T, Yoshimoto T, Ohba M, Sawada M, Kato T, Sakamoto T, Hiyama Y, Hojo H (2009) Interleukin-6 induces prostaglanding E(2) synthesis in mouse astrocytes. J Mol Neurosci. doi: 10.1007/s12031-009-9187-6 Google Scholar
  40. 40.
    Bo L, Vedeler CA, Nyland H, Trapp BD, Mork SJ (2003) Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 9:323–331. doi: 10.1191/1352458503ms917oa PubMedCrossRefGoogle Scholar
  41. 41.
    Pomeroy IM, Matthews PM, Frank JA, Jordan EK, Esiri MM (2005) Demyelinated neocortical lesions in marmoset autoimmune encephalomyelitis mimic those in multiple sclerosis. Brain 128:2713–2721. doi: 10.1093/brain/awh626 PubMedCrossRefGoogle Scholar
  42. 42.
    Storch MK, Bauer J, Linington C, Olsson T, Weissert R, Lassmann H (2006) Cortical demyelination can be modeled in specific rat models of autoimmune encephalomyelitis and is major histocompatability complex (MHC) haplotype-related. J Neuropathol Exp Neurol 65:1137–1142. doi: 10.1097/01.jnen.0000248547.13176.9d PubMedCrossRefGoogle Scholar
  43. 43.
    Brink BP, Veerhuis R, Breij EC, van der Valk P, Dijkstra CD, Bo L (2005) The pathology of multiple sclerosis is location dependent: no significant complement activation is detected in purely cortical lesions. J Neuropathol Exp Neurol 64:147–155PubMedGoogle Scholar
  44. 44.
    Evangelou N, Konz D, Esiri MM, Smith S, Palace J, Matthews PM (2001) Size-selective neuronal changes in the anterior optic pathways suggest a differential susceptibility to injury in multiple sclerosis. Brain 124:1813–1820. doi: 10.1093/brain/124.9.1813 PubMedCrossRefGoogle Scholar
  45. 45.
    Mahad D, Lassmann H, Turnbull D (2008) Review: Mitochondria and disease progression in multiple sclerosis. Neuropathol Appl Neurobiol 34:577–589. doi: 10.1111/j.1365-2990.2008.00987.x PubMedCrossRefGoogle Scholar
  46. 46.
    Mahad D, Ziabreva I, Campbell G, Lax N, White K, Hanson PS, Lassmann H, Turnbull D (2009) Mitochrondrial changes within axons in multiple sclerosis. Brain. doi: 10.1093/brain/awp046 PubMedGoogle Scholar
  47. 47.
    Mahad D, Ziabreva I, Lassmann H, Turnbull D (2009) Mitochondrial defects in acute multiple sclerosis lesions. Brain 131:1722–1735. doi: 10.1093/brain/awn105 CrossRefGoogle Scholar
  48. 48.
    Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick RA, Mirnics K, Trapp BD (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478–489. doi: 10.1002/ana.20736 PubMedCrossRefGoogle Scholar
  49. 49.
    Trapp B, Stys P (2009) Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 8:280–291. doi: 10.1016/S1474-4422(09)70043-2 PubMedCrossRefGoogle Scholar
  50. 50.
    Cleeter MW, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AH (1994) Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases. FEBS Lett 345:50–54. doi: 10.1016/0014-5793(94)00424-2 PubMedCrossRefGoogle Scholar
  51. 51.
    Lu F, Selak M, O'Connor J, Croul S, Lorenzana C, Butunoi C, Kalman B (2000) Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J Neurol Sci 177:95–103. doi: 10.1016/S0022-510X(00)00343-9 PubMedCrossRefGoogle Scholar
  52. 52.
    Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393–399. doi: 10.1093/brain/120.3.393 PubMedCrossRefGoogle Scholar
  53. 53.
    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. doi: 10.1056/NEJM199801293380502 PubMedCrossRefGoogle Scholar
  54. 54.
    Kornek B, Storch M, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive and remyelinated lesions. Am J Pathol 157:267–276PubMedGoogle Scholar
  55. 55.
    Lisak RP, Benjamins JA, Bealmear B, Nedelkoska L, Studzinski D, Redland E, Yao B, Land S (2009) Differential effects of Th1, monocyte/macrophage, and Th2 cytokine mixtures on early gene expression for molecules associated with metabolism, signaling and regulation. J Neuroinflammation 6:4. doi: 10.1186/1742-2094-6-4 PubMedCrossRefGoogle Scholar
  56. 56.
    Kotter MR, Li WW, Zhao C, Franklin RJM (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332. doi: 10.1523/JNEUROSCI.2615-05.2006 PubMedCrossRefGoogle Scholar
  57. 57.
    Rothshenker S, Reichert F, Gitik M, Haklai R, Elad-Sfadia G, Kloog Y (2008) Galectin-3/MAC-2, Ras, and PI3K activate complement receptor-3 and scavenger receptor-AI/II mediated myelin phagocytosis in microglia. Glia 56:1607–1613. doi: 10.1002/glia.20713 CrossRefGoogle Scholar
  58. 58.
    Mead RJ, Singhrao SK, Neal JW, Lassmann H, Morgan BP (2002) The membrane attack complex of complement causes severe demyelinaiton associated with acute axonal injury. J Immunol 168:458–465PubMedGoogle Scholar
  59. 59.
    Silverman BA, Carney DF, Johnston CA, Vanguri P, Shin ML (2009) Isolation of membrane attack complex of complement from myelin membranes treated with serum complement. J Neurochem 42:1024–1029. doi: 10.1111/j.1471-4159.1984.tb12706.x CrossRefGoogle Scholar
  60. 60.
    Smith ME (2001) Phagocytic properties of microglia in vitro: implications for a role in multiple sclerosis and EAE. Microsc Res Tech 54:81–94. doi: 10.1002/jemt.1123 PubMedCrossRefGoogle Scholar
  61. 61.
    Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H (2007) TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4:0675–0689CrossRefGoogle Scholar
  62. 62.
    Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, Rinker JII, Naismith RT, Panina-Bordignon P, Passini N, Galimberti D, Scarpini E, Colonna M, Cross AH (2008) Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain 131:3081–3091. doi: 10.1093/brain/awn217 PubMedCrossRefGoogle Scholar
  63. 63.
    Uehara H, Shacter E (2008) Auto-oxidation and oligomerization of protein S on the apoptotic cell surface is required for Mer tyrosine kinase-mediated phagocytosis of apoptotic cells. J Immunol 180:2522–2530PubMedGoogle Scholar
  64. 64.
    Takahashi K, Rochford CDP, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201:647–657. doi: 10.1084/jem.20041611 PubMedCrossRefGoogle Scholar
  65. 65.
    Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G (2007) TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131:1124–1136. doi: 10.1016/j.cell.2007.10.034 PubMedCrossRefGoogle Scholar
  66. 66.
    Boven LA, van Meurs M, Van Zwam M, Wierenga-Wolf A, Hintzen RQ, Boot RG, Aerts JM, Amor S, Nieewenhuis EE, Laman JD (2006) Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain 129:517–526. doi: 10.1093/brain/awh707 PubMedCrossRefGoogle Scholar
  67. 67.
    Pocock JM, Kettenmann H (2007) Neurotransmitter receptors on microglia. Trends Neurosci 30:527–535. doi: 10.1016/j.tins.2007.07.007 PubMedCrossRefGoogle Scholar
  68. 68.
    Trapp BD, Wujek J, Criste GA, Jalabi W, Yin X, Kidd GJ, Stohlman S, Ransohoff RM (2007) Evidence for synaptic stripping by cortical microglia. Glia 55:360–368. doi: 10.1002/glia.20462 PubMedCrossRefGoogle Scholar
  69. 69.
    Nikolaeva MA, Richard S, Mouihate A, Stys PK (2009) Effects of the noradrenergic system in rat white matter exposed to oxygen–glucose deprivation in vitro. J Neurosci 29:1796–1804. doi: 10.1523/JNEUROSCI.5729-08.2009 PubMedCrossRefGoogle Scholar
  70. 70.
    Bhardwaj A, Brannan T, Martinez-Tica J, Weinberger J (1990) Ischemia in the dorsal hippocampus is associated with acute extracellular release of dopamine and norepinephrine. J Neural Transm 80:195–201. doi: 10.1007/BF01245121 CrossRefGoogle Scholar
  71. 71.
    Globus MY, Busto R, Dietrich WD, Martinez E, Valdés I, Ginsberg MD (1989) Direct evidence for acute and massive norepinephrine release in the hippocampus during transient ischemia. J Cereb Blood Flow Metab 9:892–896PubMedGoogle Scholar
  72. 72.
    Perego C, Gatti S, Vetrugno GC, Marzatico F, Algeri S (1992) Correlation between electroencephalogram isoelectric time and hippocampal norepinephrine levels, measured by microdialysis, during ischemia in rats. J Neurochem 59:1257–1262. doi: 10.1111/j.1471-4159.1992.tb08435.x PubMedCrossRefGoogle Scholar
  73. 73.
    Stein SC, Cracco RQ (1982) Cortical injury without ischemia produced by topical monoamines. Stroke 13:74–83PubMedGoogle Scholar
  74. 74.
    Bickler BE, Hansen BM (1996) Alpha 2-adrenergic agonists reduce glutamate release and glutamate receptor-mediated calcium changes in hippocampal slices during hypoxia. Neuropharmacology 35:679–687. doi: 10.1016/0028-3908(96)84639-9 PubMedCrossRefGoogle Scholar
  75. 75.
    Talke P, Bickler PE (1996) Effects of dexmedetomidine on hypoxia-evoked glutamate release and glutamate receptor activity in hippocampal slices. Anesthesiology 85:551–557. doi: 10.1097/00000542-199609000-00014 PubMedCrossRefGoogle Scholar
  76. 76.
    Kalinichenko VV, Mokyr MB, Graf LH, Cohen RL, Chambers DA (1999) Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a beta-adrenergic receptor mechanism and decreased TNF-alpha gene expression. J Immunol 163:2492–2499PubMedGoogle Scholar
  77. 77.
    Ignatowski TA, Spengler RN (1995) Regulation of macrophage-derived tumor necrosis factor production by modification of adrenergic receptor sensitivity. J Neuroimmunol 61:61–70. doi: 10.1016/0165-5728(95)00074-C PubMedCrossRefGoogle Scholar
  78. 78.
    Tsai SY, Schluns KS, Le PT, McNulti JA (2001) TGF-beta1 and IL-6 expression in rat pineal gland is regulated by norepinephrine and interleukin-1 beta. Histol Histopathol 16:1135–1141PubMedGoogle Scholar
  79. 79.
    Zhu Y, Culmsee C, Roth-Eichhorn S, Krieglstein J (2001) Beta(2)-adrenoceptor stimulation enhances latent transforming growth factor beta-binding protein-1 and transforming growth factor-beta1 expression in rat hippocampus after transient forebrain ischemia. Neuroscience 107:593–602. doi: 10.1016/S0306-4522(01)00357-8 PubMedCrossRefGoogle Scholar
  80. 80.
    Pavlov VA, Tracey KJ (2006) Controlling inflammation: the cholinergic anti-inflammatory pathway. Biochem Soc Trans 34:1037–1040. doi: 10.1042/BST0341037 PubMedCrossRefGoogle Scholar
  81. 81.
    DeSimone R, Ajmone-Cat MA, Carnevale D, Minghetti L (2003) Activation of a7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures. J Neuroinflammation 2:4. doi: 10.1186/1742-2094-2-4 CrossRefGoogle Scholar
  82. 82.
    Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA, Sanberg PR, Tan J (2004) Cholinergic modulation of microglial activation by a7 nicotinic receptors. J Neurochem 89:337–343. doi: 10.1046/j.1471-4159.2004.02347.x PubMedCrossRefGoogle Scholar
  83. 83.
    Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ (2003) Nicotinic acetylcholine receptor a7 subunit is an essential regulator of inflammation. Nature 421:384–388. doi: 10.1038/nature01339 PubMedCrossRefGoogle Scholar
  84. 84.
    Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859. doi: 10.1038/nature01321 PubMedCrossRefGoogle Scholar
  85. 85.
    Park HJ, Lee PH, Ahn YW, Choi YJ, Lee G, Lee DY, Chung ES, Jin BK (2007) Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. Eur J Neurosci 26:79–89. doi: 10.1111/j.1460-9568.2007.05636.x PubMedCrossRefGoogle Scholar
  86. 86.
    Wang M-J, Lin S-Z, Kuo J-S, Huang H-Y, Tzeng S-F, Liao C-H, Chen D-C, Chen W-F (2007) Urocortin modulates inflammatory response and neurotoxicity induced by microglial activation. J Immunol 1433:6204–6214Google Scholar
  87. 87.
    Hundhausen C, Misztela D, Berkhout TA, Broadway N, Saftig P, Reiss K, Hartmann D, Fahrenholz F, Postina R, Matthews V, Kallen KJ, Rose-John S, Ludwig A (2003) The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell–cell adhesion. Blood 102:1186–1195. doi: 10.1182/blood-2002-12-3775 PubMedCrossRefGoogle Scholar
  88. 88.
    Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglia neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924. doi: 10.1038/nn1715 PubMedCrossRefGoogle Scholar
  89. 89.
    Mizuno T, Kawanokuchi J, Numata K, Suzumura A (2003) Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res 979:65–70. doi: 10.1016/S0006-8993(03)02867-1 PubMedCrossRefGoogle Scholar
  90. 90.
    Neumann H, Misgeld T, Matsumoro K, Wekerle H (1998) Neurotrophins inhibit class II inducibility of microglia: Involvement of the p75 receptor. Proc Natl Acad Sci USA 95:5779–5784. doi: 10.1073/pnas.95.10.5779 PubMedCrossRefGoogle Scholar
  91. 91.
    Tzeng SF, Huang HY (2003) Downregulation of inducible nitric oxide synthetase by neurotrophin-3 in microglia. J Cell Biochem 90:227–233. doi: 10.1002/jcb.10658 PubMedCrossRefGoogle Scholar
  92. 92.
    Mir M, Tolosa L, Asensio VJ, Lladó J, Olmos G (2008) Complementary roles of tumor necrosis factor alpha and interferon gamma in inducible microglial nitric oxide generation. J Neuroimmunol 204:101–109. doi: 10.1016/j.jneuroim.2008.07.002 PubMedCrossRefGoogle Scholar
  93. 93.
    Arnett HA, Hellendall RP, Matsushima GK, Suzuki K, Laubach VE, Sherman P, Ting JP (2002) The protective role of nitric oxide in a neurotoxicant-induced demyelinating model. J Immunol 168:427–433PubMedGoogle Scholar
  94. 94.
    Jeon S-B, Yoon HJ, Park S-H, Kim I-H, Park EJ (2008) Sulfatide, a major lipid component of myelin sheath, activates inflamamtory responses as an endogenous stimulator in brain-resident immune cells. J Immunol 181:8077–8087PubMedGoogle Scholar
  95. 95.
    Johnston JB, Silva C, Holden J, Warren KG, Clark AW, Power C (2001) Monocyte activation and differentiation augment human endogenous retrovirus expresssion: implications for inflammatory brain diseases. Ann Neurol 50:434–442. doi: 10.1002/ana.1131 PubMedCrossRefGoogle Scholar
  96. 96.
    Perron H, Lazarini F, Ruprecht K, Péchoux-Longin C, Seilhean D, Sazdovitch V, Créange A, Battail-Poirot N, Sibai G, Santoro L, Jolivet M, Darlix JL, Rieckmann P, Arzberger T, Hauw JJ, Lassmann H (2005) Human endogenous retrovirus (HERV)-W Env and GAG proteins: physiological expression in human brain and pathophysiological modulation in multiple sclerosis lesions. J Neurovirol 11:23–33. doi: 10.1080/13550280590901741 PubMedCrossRefGoogle Scholar
  97. 97.
    Anthony JM, van Marle G, Opii W, Butterfield DA, Mallet F, Wee Yong V, Wallace JL, Deacon RM, Warren K, Power C (2004) Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat Neurosci 7:1088–1095. doi: 10.1038/nn1319 CrossRefGoogle Scholar
  98. 98.
    Rolland A, Jouvin-Marche E, Viret C, Faure M, Perron H, Marche PN (2006) The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses. J Immunol 176:7636–7644PubMedGoogle Scholar
  99. 99.
    Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress, and the biology of ageing. Nature 408:239–247. doi: 10.1038/35041687 PubMedCrossRefGoogle Scholar
  100. 100.
    Monti B, Virgili M, Contestabile A (2004) Alterations of markers related to synaptic function in aging rat brain, in normal conditions or under conditions of long-term dietary manipulation. Neurochem Int 44:579–584. doi: 10.1016/j.neuint.2003.10.007 PubMedCrossRefGoogle Scholar
  101. 101.
    Segovia G, Porras A, Del Arco A, Mora F (2001) Glutamatergic neurotransmission in aging: a critical perspective. Mech Ageing Dev 122:1–29. doi: 10.1016/S0047-6374(00)00225-6 PubMedCrossRefGoogle Scholar
  102. 102.
    Amenta F, Bronzetti E, Sabbatini M, Vega JA (1998) Astrocyte changes in aging cerebral cortex and hippocampus: a quantitative immunohistochemical study. Microsc Res Tech 43:29–33. doi: 10.1002/(SICI)1097-0029(19981001)43:1<29::AID-JEMT5>3.0.CO;2-H PubMedCrossRefGoogle Scholar
  103. 103.
    Finch CE, Morgan TE, Rozovsky I, Xie Z, Weindruch R, Prolla T (2002) Microglia and aging in the brain. In: Streit WJ (ed) Microglia in the regenerating and degenerating CNS. Springer Verlag, Gainesville, pp 275–305Google Scholar
  104. 104.
    Finch CE (2002) Neurons, glia, and plasticity in normal brain aging. Adv Gerontol 10:35–39PubMedGoogle Scholar
  105. 105.
    Perry VH, Matyszak MK, Fearn S (1993) Altered antigen expression of microglia in the aged rodent CNS. Glia 7:60–67. doi: 10.1002/glia.440070111 PubMedCrossRefGoogle Scholar
  106. 106.
    Wasserman JK, Yang H, Schlichter LC (2008) Glial responses, neuron death, and lesion resolution after intracerebral hemorrhage in young vs. aged rats. Eur J Neurosci 28:1316–1328. doi: 10.1111/j.1460-9568.2008.06442.x PubMedCrossRefGoogle Scholar
  107. 107.
    Campuzano O, Castillo-Ruiz MM, Acarin L, Castellano B, Gonzalez B (2009) Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury-induced cytokine response after excitotoxic damage. J Neurosci Res. doi: 10.1002/jnr.22074 PubMedGoogle Scholar
  108. 108.
    Campuzano O, Castillo-Ruiz MM, Acarin L, Castellano B, Gonzales B (2008) Distinct pattern of microglial response, cyclooxygenase-2, and inducible nitric oxide synthase expression in the aged rat brain after excitotoxic damage. J Neurosci Res 86:3170–3183. doi: 10.1002/jnr.21751 PubMedCrossRefGoogle Scholar
  109. 109.
    Sparkman NL, Johnson RW (2008) Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation 15:323–330. doi: 10.1159/000156474 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of NeuroimmunologyMedical University Vienna, Center for Brain ResearchViennaAustria

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