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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2003 Oct 29;358(1438):1669–1677. doi: 10.1098/rstb.2003.1358

Inflammation in central nervous system injury.

Stuart M Allan 1, Nancy J Rothwell 1
PMCID: PMC1693261  PMID: 14561325

Abstract

Inflammation is a key component of host defence responses to peripheral inflammation and injury, but it is now also recognized as a major contributor to diverse, acute and chronic central nervous system (CNS) disorders. Expression of inflammatory mediators including complement, adhesion molecules, cyclooxygenase enzymes and their products and cytokines is increased in experimental and clinical neurodegenerative disease, and intervention studies in experimental animals suggest that several of these factors contribute directly to neuronal injury. Most notably, specific cytokines, such as interleukin-1 (IL-1), have been implicated heavily in acute neurodegeneration, such as stroke and head injury. In spite of their diverse presentation, common inflammatory mechanisms may contribute to many neurodegenerative disorders and in some (e.g. multiple sclerosis) inflammatory modulators are in clinical use. Inflammation may have beneficial as well as detrimental actions in the CNS, particularly in repair and recovery. Nevertheless, several anti-inflammatory targets have been identified as putative treatments for CNS disorders, initially in acute conditions, but which may also be appropriate to chronic neurodegenerative conditions.

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Selected References

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  1. Allan S. M., Rothwell N. J. Cytokines and acute neurodegeneration. Nat Rev Neurosci. 2001 Oct;2(10):734–744. doi: 10.1038/35094583. [DOI] [PubMed] [Google Scholar]
  2. Arend William P. The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev. 2002 Aug-Oct;13(4-5):323–340. doi: 10.1016/s1359-6101(02)00020-5. [DOI] [PubMed] [Google Scholar]
  3. Baumann N., Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev. 2001 Apr;81(2):871–927. doi: 10.1152/physrev.2001.81.2.871. [DOI] [PubMed] [Google Scholar]
  4. Benveniste E. N., Benos D. J. TNF-alpha- and IFN-gamma-mediated signal transduction pathways: effects on glial cell gene expression and function. FASEB J. 1995 Dec;9(15):1577–1584. doi: 10.1096/fasebj.9.15.8529837. [DOI] [PubMed] [Google Scholar]
  5. Bettelli E., Nicholson L. B. The role of cytokines in experimental autoimmune encephalomyelitis. Arch Immunol Ther Exp (Warsz) 2000;48(5):389–398. [PubMed] [Google Scholar]
  6. Bitsch A., Schuchardt J., Bunkowski S., Kuhlmann T., Brück W. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain. 2000 Jun;123(Pt 6):1174–1183. doi: 10.1093/brain/123.6.1174. [DOI] [PubMed] [Google Scholar]
  7. Blamire A. M., Anthony D. C., Rajagopalan B., Sibson N. R., Perry V. H., Styles P. Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study. J Neurosci. 2000 Nov 1;20(21):8153–8159. doi: 10.1523/JNEUROSCI.20-21-08153.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bonmann E., Suschek C., Spranger M., Kolb-Bachofen V. The dominant role of exogenous or endogenous interleukin-1 beta on expression and activity of inducible nitric oxide synthase in rat microvascular brain endothelial cells. Neurosci Lett. 1997 Jul 18;230(2):109–112. doi: 10.1016/s0304-3940(97)00485-0. [DOI] [PubMed] [Google Scholar]
  9. Bonventre J. V. Roles of phospholipases A2 in brain cell and tissue injury associated with ischemia and excitotoxicity. J Lipid Mediat Cell Signal. 1997 Jul;16(3):199–208. doi: 10.1016/s0929-7855(97)00014-x. [DOI] [PubMed] [Google Scholar]
  10. Boutin H., LeFeuvre R. A., Horai R., Asano M., Iwakura Y., Rothwell N. J. Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci. 2001 Aug 1;21(15):5528–5534. doi: 10.1523/JNEUROSCI.21-15-05528.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bresnihan B. The safety and efficacy of interleukin-1 receptor antagonist in the treatment of rheumatoid arthritis. Semin Arthritis Rheum. 2001 Apr;30(5 Suppl 2):17–20. doi: 10.1053/sarh.2001.23701. [DOI] [PubMed] [Google Scholar]
  12. Chen Yongmei, Swanson Raymond A. Astrocytes and brain injury. J Cereb Blood Flow Metab. 2003 Feb;23(2):137–149. doi: 10.1097/01.WCB.0000044631.80210.3C. [DOI] [PubMed] [Google Scholar]
  13. Clark W. M., Rinker L. G., Lessov N. S., Hazel K., Hill J. K., Stenzel-Poore M., Eckenstein F. Lack of interleukin-6 expression is not protective against focal central nervous system ischemia. Stroke. 2000 Jul;31(7):1715–1720. doi: 10.1161/01.str.31.7.1715. [DOI] [PubMed] [Google Scholar]
  14. Coclet-Ninin J., Dayer J. M., Burger D. Interferon-beta not only inhibits interleukin-1beta and tumor necrosis factor-alpha but stimulates interleukin-1 receptor antagonist production in human peripheral blood mononuclear cells. Eur Cytokine Netw. 1997 Dec;8(4):345–349. [PubMed] [Google Scholar]
  15. Couraud P. O. Interactions between lymphocytes, macrophages, and central nervous system cells. J Leukoc Biol. 1994 Sep;56(3):407–415. doi: 10.1002/jlb.56.3.407. [DOI] [PubMed] [Google Scholar]
  16. Członkowska Anna, Kurkowska-Jastrzebska Iwona, Członkowski Andrzej, Peter Doris, Stefano George B. Immune processes in the pathogenesis of Parkinson's disease - a potential role for microglia and nitric oxide. Med Sci Monit. 2002 Aug;8(8):RA165–RA177. [PubMed] [Google Scholar]
  17. Dewar D., Yam P., McCulloch J. Drug development for stroke: importance of protecting cerebral white matter. Eur J Pharmacol. 1999 Jun 30;375(1-3):41–50. doi: 10.1016/s0014-2999(99)00280-0. [DOI] [PubMed] [Google Scholar]
  18. Dinarello C. A. Cytokines as endogenous pyrogens. J Infect Dis. 1999 Mar;179 (Suppl 2):S294–S304. doi: 10.1086/513856. [DOI] [PubMed] [Google Scholar]
  19. Du Yangzhou, Dreyfus Cheryl F. Oligodendrocytes as providers of growth factors. J Neurosci Res. 2002 Jun 15;68(6):647–654. doi: 10.1002/jnr.10245. [DOI] [PubMed] [Google Scholar]
  20. Emsley Hedley C. A., Tyrrell Pippa J. Inflammation and infection in clinical stroke. J Cereb Blood Flow Metab. 2002 Dec;22(12):1399–1419. doi: 10.1097/01.WCB.0000037880.62590.28. [DOI] [PubMed] [Google Scholar]
  21. Erkinjuntti T. Diagnosis and management of vascular cognitive impairment and dementia. J Neural Transm Suppl. 2002;(63):91–109. doi: 10.1007/978-3-7091-6137-1_6. [DOI] [PubMed] [Google Scholar]
  22. Fisher Marc, Brott Thomas G. Emerging therapies for acute ischemic stroke: new therapies on trial. Stroke. 2003 Feb;34(2):359–361. doi: 10.1161/01.str.0000054627.69159.c2. [DOI] [PubMed] [Google Scholar]
  23. Furlan R., Brambilla E., Ruffini F., Poliani P. L., Bergami A., Marconi P. C., Franciotta D. M., Penna G., Comi G., Adorini L. Intrathecal delivery of IFN-gamma protects C57BL/6 mice from chronic-progressive experimental autoimmune encephalomyelitis by increasing apoptosis of central nervous system-infiltrating lymphocytes. J Immunol. 2001 Aug 1;167(3):1821–1829. doi: 10.4049/jimmunol.167.3.1821. [DOI] [PubMed] [Google Scholar]
  24. Garden Gwenn A. Microglia in human immunodeficiency virus-associated neurodegeneration. Glia. 2002 Nov;40(2):240–251. doi: 10.1002/glia.10155. [DOI] [PubMed] [Google Scholar]
  25. Gary D. S., Bruce-Keller A. J., Kindy M. S., Mattson M. P. Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor. J Cereb Blood Flow Metab. 1998 Dec;18(12):1283–1287. doi: 10.1097/00004647-199812000-00001. [DOI] [PubMed] [Google Scholar]
  26. Gasque P., Dean Y. D., McGreal E. P., VanBeek J., Morgan B. P. Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology. 2000 Aug;49(1-2):171–186. doi: 10.1016/s0162-3109(00)80302-1. [DOI] [PubMed] [Google Scholar]
  27. Gebicke-Haerter P. J. Microglia in neurodegeneration: molecular aspects. Microsc Res Tech. 2001 Jul 1;54(1):47–58. doi: 10.1002/jemt.1120. [DOI] [PubMed] [Google Scholar]
  28. Ginsberg M. D., Busto R. Combating hyperthermia in acute stroke: a significant clinical concern. Stroke. 1998 Feb;29(2):529–534. doi: 10.1161/01.str.29.2.529. [DOI] [PubMed] [Google Scholar]
  29. Goldberg Mark P., Ransom Bruce R. New light on white matter. Stroke. 2003 Feb;34(2):330–332. doi: 10.1161/01.str.0000054048.22626.b9. [DOI] [PubMed] [Google Scholar]
  30. Griffin W. Sue T., Mrak Robert E. Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease. J Leukoc Biol. 2002 Aug;72(2):233–238. [PMC free article] [PubMed] [Google Scholar]
  31. Grilli M., Barbieri I., Basudev H., Brusa R., Casati C., Lozza G., Ongini E. Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage. Eur J Neurosci. 2000 Jul;12(7):2265–2272. doi: 10.1046/j.1460-9568.2000.00090.x. [DOI] [PubMed] [Google Scholar]
  32. Guterman A., Smith R. W. Neurological sequelae of boxing. Sports Med. 1987 May-Jun;4(3):194–210. doi: 10.2165/00007256-198704030-00004. [DOI] [PubMed] [Google Scholar]
  33. Gutierrez E. G., Banks W. A., Kastin A. J. Blood-borne interleukin-1 receptor antagonist crosses the blood-brain barrier. J Neuroimmunol. 1994 Dec;55(2):153–160. doi: 10.1016/0165-5728(94)90005-1. [DOI] [PubMed] [Google Scholar]
  34. Hanisch Uwe-Karsten. Microglia as a source and target of cytokines. Glia. 2002 Nov;40(2):140–155. doi: 10.1002/glia.10161. [DOI] [PubMed] [Google Scholar]
  35. Hara H., Fink K., Endres M., Friedlander R. M., Gagliardini V., Yuan J., Moskowitz M. A. Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein. J Cereb Blood Flow Metab. 1997 Apr;17(4):370–375. doi: 10.1097/00004647-199704000-00002. [DOI] [PubMed] [Google Scholar]
  36. Hedtjärn Maj, Leverin Anna-Lena, Eriksson Kristina, Blomgren Klas, Mallard Carina, Hagberg Henrik. Interleukin-18 involvement in hypoxic-ischemic brain injury. J Neurosci. 2002 Jul 15;22(14):5910–5919. doi: 10.1523/JNEUROSCI.22-14-05910.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Hohlfeld R., Wiendl H. The ups and downs of multiple sclerosis therapeutics. Ann Neurol. 2001 Mar;49(3):281–284. [PubMed] [Google Scholar]
  38. Holmin S., Mathiesen T. Intracerebral administration of interleukin-1beta and induction of inflammation, apoptosis, and vasogenic edema. J Neurosurg. 2000 Jan;92(1):108–120. doi: 10.3171/jns.2000.92.1.0108. [DOI] [PubMed] [Google Scholar]
  39. Iadecola C., Niwa K., Nogawa S., Zhao X., Nagayama M., Araki E., Morham S., Ross M. E. Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1294–1299. doi: 10.1073/pnas.98.3.1294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Iadecola C., Zhang F., Casey R., Nagayama M., Ross M. E. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci. 1997 Dec 1;17(23):9157–9164. doi: 10.1523/JNEUROSCI.17-23-09157.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Jander S., Schroeter M., Peters O., Witte O. W., Stoll G. Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain. J Cereb Blood Flow Metab. 2001 Mar;21(3):218–225. doi: 10.1097/00004647-200103000-00005. [DOI] [PubMed] [Google Scholar]
  42. Janus C., Westaway D. Transgenic mouse models of Alzheimer's disease. Physiol Behav. 2001 Aug;73(5):873–886. doi: 10.1016/s0031-9384(01)00524-8. [DOI] [PubMed] [Google Scholar]
  43. Jellinger K. A., Paulus W., Wrocklage C., Litvan I. Effects of closed traumatic brain injury and genetic factors on the development of Alzheimer's disease. Eur J Neurol. 2001 Nov;8(6):707–710. doi: 10.1046/j.1468-1331.2001.00322.x. [DOI] [PubMed] [Google Scholar]
  44. Jungo F., Dayer J. M., Modoux C., Hyka N., Burger D. IFN-beta inhibits the ability of T lymphocytes to induce TNF-alpha and IL-1beta production in monocytes upon direct cell-cell contact. Cytokine. 2001 Jun 7;14(5):272–282. doi: 10.1006/cyto.2001.0884. [DOI] [PubMed] [Google Scholar]
  45. Kalaria Raj. Similarities between Alzheimer's disease and vascular dementia. J Neurol Sci. 2002 Nov 15;203-204:29–34. doi: 10.1016/s0022-510x(02)00256-3. [DOI] [PubMed] [Google Scholar]
  46. Kanemoto K., Kawasaki J., Miyamoto T., Obayashi H., Nishimura M. Interleukin (IL)1beta, IL-1alpha, and IL-1 receptor antagonist gene polymorphisms in patients with temporal lobe epilepsy. Ann Neurol. 2000 May;47(5):571–574. [PubMed] [Google Scholar]
  47. Legos Jeffrey J., Tuma Ronald F., Barone Frank C. Pharmacological interventions for stroke: failures and future. Expert Opin Investig Drugs. 2002 May;11(5):603–614. doi: 10.1517/13543784.11.5.603. [DOI] [PubMed] [Google Scholar]
  48. Li Yuekui, Liu Ling, Barger Steven W., Griffin W. Sue T. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci. 2003 Mar 1;23(5):1605–1611. doi: 10.1523/JNEUROSCI.23-05-01605.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Link H., Xiao B. G. Rat models as tool to develop new immunotherapies. Immunol Rev. 2001 Dec;184:117–128. doi: 10.1034/j.1600-065x.2001.1840111.x. [DOI] [PubMed] [Google Scholar]
  50. Liu J. S., Amaral T. D., Brosnan C. F., Lee S. C. IFNs are critical regulators of IL-1 receptor antagonist and IL-1 expression in human microglia. J Immunol. 1998 Aug 15;161(4):1989–1996. [PubMed] [Google Scholar]
  51. Liu X. H., Kwon D., Schielke G. P., Yang G. Y., Silverstein F. S., Barks J. D. Mice deficient in interleukin-1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage. J Cereb Blood Flow Metab. 1999 Oct;19(10):1099–1108. doi: 10.1097/00004647-199910000-00006. [DOI] [PubMed] [Google Scholar]
  52. Lou J., Lucas R., Grau G. E. Pathogenesis of cerebral malaria: recent experimental data and possible applications for humans. Clin Microbiol Rev. 2001 Oct;14(4):810-20, table of contents. doi: 10.1128/CMR.14.4.810-820.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Lye T. C., Shores E. A. Traumatic brain injury as a risk factor for Alzheimer's disease: a review. Neuropsychol Rev. 2000 Jun;10(2):115–129. doi: 10.1023/a:1009068804787. [DOI] [PubMed] [Google Scholar]
  54. Maimone D., Dominici R., Grimaldi L. M. Pharmacogenomics of neurodegenerative diseases. Eur J Pharmacol. 2001 Feb 9;413(1):11–29. doi: 10.1016/s0014-2999(00)00939-0. [DOI] [PubMed] [Google Scholar]
  55. Matyszak M. K. Inflammation in the CNS: balance between immunological privilege and immune responses. Prog Neurobiol. 1998 Oct;56(1):19–35. doi: 10.1016/s0301-0082(98)00014-8. [DOI] [PubMed] [Google Scholar]
  56. McGeer P. L., McGeer E. G. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve. 2002 Oct;26(4):459–470. doi: 10.1002/mus.10191. [DOI] [PubMed] [Google Scholar]
  57. McGeer P. L., McGeer E. G. Polymorphisms in inflammatory genes and the risk of Alzheimer disease. Arch Neurol. 2001 Nov;58(11):1790–1792. doi: 10.1001/archneur.58.11.1790. [DOI] [PubMed] [Google Scholar]
  58. McGeer Patrick L., McGeer Edith G. Local neuroinflammation and the progression of Alzheimer's disease. J Neurovirol. 2002 Dec;8(6):529–538. doi: 10.1080/13550280290100969. [DOI] [PubMed] [Google Scholar]
  59. McGeer Patrick L., Yasojima Koji, McGeer Edith G. Association of interleukin-1 beta polymorphisms with idiopathic Parkinson's disease. Neurosci Lett. 2002 Jun 21;326(1):67–69. doi: 10.1016/s0304-3940(02)00300-2. [DOI] [PubMed] [Google Scholar]
  60. Merrill J. E., Ignarro L. J., Sherman M. P., Melinek J., Lane T. E. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J Immunol. 1993 Aug 15;151(4):2132–2141. [PubMed] [Google Scholar]
  61. Narayan Raj K., Michel Mary Ellen, Ansell Beth, Baethmann Alex, Biegon Anat, Bracken Michael B., Bullock M. Ross, Choi Sung C., Clifton Guy L., Contant Charles F. Clinical trials in head injury. J Neurotrauma. 2002 May;19(5):503–557. doi: 10.1089/089771502753754037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Nguyen Minh Dang, Julien Jean-Pierre, Rivest Serge. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci. 2002 Mar;3(3):216–227. doi: 10.1038/nrn752. [DOI] [PubMed] [Google Scholar]
  63. Ohtaki Hirokazu, Funahashi Hisayuki, Dohi Kenji, Oguro Takiko, Horai Reiko, Asano Masahide, Iwakura Yoichiro, Yin Li, Matsunaga Masaji, Goto Noboru. Suppression of oxidative neuronal damage after transient middle cerebral artery occlusion in mice lacking interleukin-1. Neurosci Res. 2003 Mar;45(3):313–324. doi: 10.1016/s0168-0102(02)00238-9. [DOI] [PubMed] [Google Scholar]
  64. Olsson T., Zhi W. W., Höjeberg B., Kostulas V., Jiang Y. P., Anderson G., Ekre H. P., Link H. Autoreactive T lymphocytes in multiple sclerosis determined by antigen-induced secretion of interferon-gamma. J Clin Invest. 1990 Sep;86(3):981–985. doi: 10.1172/JCI114800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Pasinetti Giulio Maria. From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: the role of NSAIDs and cyclooxygenase in beta-amyloidosis and clinical dementia. J Alzheimers Dis. 2002 Oct;4(5):435–445. doi: 10.3233/jad-2002-4510. [DOI] [PubMed] [Google Scholar]
  66. Perry V. H., Bell M. D., Brown H. C., Matyszak M. K. Inflammation in the nervous system. Curr Opin Neurobiol. 1995 Oct;5(5):636–641. doi: 10.1016/0959-4388(95)80069-7. [DOI] [PubMed] [Google Scholar]
  67. Perry V. H., Bolton S. J., Anthony D. C., Betmouni S. The contribution of inflammation to acute and chronic neurodegeneration. Res Immunol. 1998 Sep-Oct;149(7-8):721–725. doi: 10.1016/s0923-2494(99)80046-7. [DOI] [PubMed] [Google Scholar]
  68. Perry V. Hugh, Newman Tracey A., Cunningham Colm. The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci. 2003 Feb;4(2):103–112. doi: 10.1038/nrn1032. [DOI] [PubMed] [Google Scholar]
  69. Petty Margaret A., Lo Eng H. Junctional complexes of the blood-brain barrier: permeability changes in neuroinflammation. Prog Neurobiol. 2002 Dec;68(5):311–323. doi: 10.1016/s0301-0082(02)00128-4. [DOI] [PubMed] [Google Scholar]
  70. Prat Alexandre, Biernacki Katarzyna, Lavoie Jean-Francois, Poirier Josee, Duquette Pierre, Antel Jack P. Migration of multiple sclerosis lymphocytes through brain endothelium. Arch Neurol. 2002 Mar;59(3):391–397. doi: 10.1001/archneur.59.3.391. [DOI] [PubMed] [Google Scholar]
  71. Quagliarello V. J., Wispelwey B., Long W. J., Jr, Scheld W. M. Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor. J Clin Invest. 1991 Apr;87(4):1360–1366. doi: 10.1172/JCI115140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Quan N., Herkenham M. Connecting cytokines and brain: a review of current issues. Histol Histopathol. 2002 Jan;17(1):273–288. doi: 10.14670/HH-17.273. [DOI] [PubMed] [Google Scholar]
  73. Raivich G., Bohatschek M., Kloss C. U., Werner A., Jones L. L., Kreutzberg G. W. Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res Brain Res Rev. 1999 Jul;30(1):77–105. doi: 10.1016/s0165-0173(99)00007-7. [DOI] [PubMed] [Google Scholar]
  74. Rieckmann P., Albrecht M., Kitze B., Weber T., Tumani H., Broocks A., Lüer W., Helwig A., Poser S. Tumor necrosis factor-alpha messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity. Ann Neurol. 1995 Jan;37(1):82–88. doi: 10.1002/ana.410370115. [DOI] [PubMed] [Google Scholar]
  75. Rossi S., Zanier E. R., Mauri I., Columbo A., Stocchetti N. Brain temperature, body core temperature, and intracranial pressure in acute cerebral damage. J Neurol Neurosurg Psychiatry. 2001 Oct;71(4):448–454. doi: 10.1136/jnnp.71.4.448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Rothwell N. J., Luheshi G. N. Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci. 2000 Dec;23(12):618–625. doi: 10.1016/s0166-2236(00)01661-1. [DOI] [PubMed] [Google Scholar]
  77. Rudmann D. G., Durham S. K. Utilization of genetically altered animals in the pharmaceutical industry. Toxicol Pathol. 1999 Jan-Feb;27(1):111–114. doi: 10.1177/019262339902700121. [DOI] [PubMed] [Google Scholar]
  78. Schulte Thorsten, Schöls Ludger, Müller Thomas, Woitalla Dirk, Berger Klaus, Krüger Rejko. Polymorphisms in the interleukin-1 alpha and beta genes and the risk for Parkinson's disease. Neurosci Lett. 2002 Jun 21;326(1):70–72. doi: 10.1016/s0304-3940(02)00301-4. [DOI] [PubMed] [Google Scholar]
  79. Soriano S. G., Lipton S. A., Wang Y. F., Xiao M., Springer T. A., Gutierrez-Ramos J. C., Hickey P. R. Intercellular adhesion molecule-1-deficient mice are less susceptible to cerebral ischemia-reperfusion injury. Ann Neurol. 1996 May;39(5):618–624. doi: 10.1002/ana.410390511. [DOI] [PubMed] [Google Scholar]
  80. Streit Wolfgang J. Microglia as neuroprotective, immunocompetent cells of the CNS. Glia. 2002 Nov;40(2):133–139. doi: 10.1002/glia.10154. [DOI] [PubMed] [Google Scholar]
  81. Szelényi J. Cytokines and the central nervous system. Brain Res Bull. 2001 Mar 1;54(4):329–338. doi: 10.1016/s0361-9230(01)00428-2. [DOI] [PubMed] [Google Scholar]
  82. Touzani Omar, Boutin Herve, LeFeuvre Rosalind, Parker Lisa, Miller Andy, Luheshi Giamal, Rothwell Nancy. Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type I receptor. J Neurosci. 2002 Jan 1;22(1):38–43. doi: 10.1523/JNEUROSCI.22-01-00038.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Van Everbroeck B., Dewulf E., Pals Ph, Lübke U., Martin J-J, Cras P. The role of cytokines, astrocytes, microglia and apoptosis in Creutzfeldt-Jakob disease. Neurobiol Aging. 2002 Jan-Feb;23(1):59–64. doi: 10.1016/s0197-4580(01)00236-6. [DOI] [PubMed] [Google Scholar]
  84. Vartanian T., Li Y., Zhao M., Stefansson K. Interferon-gamma-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis. Mol Med. 1995 Nov;1(7):732–743. [PMC free article] [PubMed] [Google Scholar]
  85. Vezzani A., Conti M., De Luigi A., Ravizza T., Moneta D., Marchesi F., De Simoni M. G. Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J Neurosci. 1999 Jun 15;19(12):5054–5065. doi: 10.1523/JNEUROSCI.19-12-05054.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Wong D., Dorovini-Zis K. Upregulation of intercellular adhesion molecule-1 (ICAM-1) expression in primary cultures of human brain microvessel endothelial cells by cytokines and lipopolysaccharide. J Neuroimmunol. 1992 Jul;39(1-2):11–21. doi: 10.1016/0165-5728(92)90170-p. [DOI] [PubMed] [Google Scholar]
  87. Wyss-Coray Tony, Mucke Lennart. Inflammation in neurodegenerative disease--a double-edged sword. Neuron. 2002 Aug 1;35(3):419–432. doi: 10.1016/s0896-6273(02)00794-8. [DOI] [PubMed] [Google Scholar]
  88. Zandi P. P., Breitner J. C. Do NSAIDs prevent Alzheimer's disease? And, if so, why? The epidemiological evidence. Neurobiol Aging. 2001 Nov-Dec;22(6):811–817. doi: 10.1016/s0197-4580(01)00297-4. [DOI] [PubMed] [Google Scholar]
  89. de Souza J. Brian, Riley Eleanor M. Cerebral malaria: the contribution of studies in animal models to our understanding of immunopathogenesis. Microbes Infect. 2002 Mar;4(3):291–300. doi: 10.1016/s1286-4579(02)01541-1. [DOI] [PubMed] [Google Scholar]
  90. del Zoppo G., Ginis I., Hallenbeck J. M., Iadecola C., Wang X., Feuerstein G. Z. Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol. 2000 Jan;10(1):95–112. doi: 10.1111/j.1750-3639.2000.tb00247.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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