Neuroprotection in multiple sclerosis: A therapeutic challenge for the next decade

Pharmacology and Therapeutics

Volumn 126, Issue 1, 2010, Pages 82-93

  Van der Walt, Anneke ^a,c   Butzkueven, Helmut ^a,b,c   Kolbe, Scott ^b,c   Marriott, Mark ^a,b   Alexandrou, Estella ^c   Gresle, Melissa ^b   Egan, Gary ^b,c   Kilpatrick, Trevor ^a,b,c  

^a ROYAL MELBOURNE HOSPITAL   (Australia)

^b FLOREY INSTITUTE OF NEUROSCIENCE AND MENTAL HEALTH   (Australia)

^c UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

Axonal degeneration; Cellular protection; Multiple sclerosis; Neuroprotection; Neuroprotective therapy

Indexed keywords

ADENOSINE TRIPHOSPHATASE (POTASSIUM SODIUM); BEPRIDIL; BETA INTERFERON; BETA1A INTERFERON; CALCIUM CHANNEL BLOCKING AGENT; CARBAMAZEPINE; FLECAINIDE; GLATIRAMER; GLUTAMATE RECEPTOR ANTAGONIST; GLUTAMIC ACID; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IMMUNOMODULATING AGENT; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERFERON BETA SERINE; LAMOTRIGINE; MITOXANTRONE; MYELIN; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NATALIZUMAB; NEUROPROTECTIVE AGENT; NIFEDIPINE; NIMODIPINE; NITRENDIPINE; PHENYTOIN; PLACEBO; RYANODINE RECEPTOR; SODIUM CALCIUM EXCHANGE PROTEIN; SODIUM CHANNEL BLOCKING AGENT; TOPIRAMATE; UNINDEXED DRUG;

AXONAL INJURY; BRAIN ATROPHY; CLINICAL STUDY; CLINICAL TRIAL; DEGENERATIVE DISEASE; DEMYELINATION; DRUG RECEPTOR BINDING; HUMAN; MULTIPLE SCLEROSIS; NERVE FIBER DEGENERATION; NEUROPATHOLOGY; NEUROPROTECTION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OPTIC NEURITIS; PRIORITY JOURNAL; REVIEW; TREATMENT OUTCOME;

ANIMALS; AXONS; CLINICAL TRIALS AS TOPIC; DRUG EVALUATION, PRECLINICAL; HUMANS; INFLAMMATION; MULTIPLE SCLEROSIS; NERVE DEGENERATION; NEUROPROTECTIVE AGENTS;

EID: 77649274969     PISSN: 01637258     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2010.01.006     Document Type: Review

References (190)

1. Agnello D., Bigini P., Villa P., Mennini T., Cerami A., Brines M.L., et al. Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis. Brain Res 952 1 (2002) 128-134
2. Altmann D.R., Jasperse B., Barkhof F., Beckmann K., Filippi M., Kappos L.D., et al. Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis. Neurology 72 7 (2009) 595-601
3. Baier M.L., Cutter G.R., Rudick R.A., Miller D., Cohen J.A., Weinstock-Guttman B., et al. Low-contrast letter acuity testing captures visual dysfunction in patients with multiple sclerosis. Neurology 64 6 (2005) 992-995
4. Balcer L.J. Clinical outcome measures for research in multiple sclerosis. J Neuroophthalmol 21 4 (2001) 296-301
5. Balcer L.J. Clinical practice. Optic neuritis. N Engl J Med 354 12 (2006) 1273-1280
6. Barnett M.H., and Prineas J.W. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 55 4 (2004) 458-468
7. Bechtold D.A., and Smith K.J. Sodium-mediated axonal degeneration in inflammatory demyelinating disease. J Neurol Sci 233 1-2 (2005) 27-35
8. Bechtold D.A., Kapoor R., and Smith K.J. Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann Neurol 55 5 (2004) 607-616
9. Bechtold D.A., Miller S.J., Dawson A.C., Sun Y., Kapoor R., Berry D., et al. Axonal protection achieved in a model of multiple sclerosis using lamotrigine. Journal of Neurology 253 12 (2006) 1542-1551
10. Beck R.W., Cleary P.A., Anderson Jr. M.M., Keltner J.L., Shults W.T., Kaufman D.I., et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med 326 9 (1992) 581-588
11. Bettelli E., Pagany M., Weiner H.L., Linington C., Sobel R.A., and Kuchroo V.K. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J Exp Med 197 9 (2003) 1073-1081
12. Bielekova B., and Martin R. Development of biomarkers in multiple sclerosis. Brain 127 Pt 7 (2004) 1463-1478
13. Birnbaum G., Cree B., Altafullah I., Zinser M., and Reder A.T. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology 71 18 (2008) 1390-1395
14. Bitsch A., Schuchardt J., Bunkowski S., Kuhlmann T., and Bruck W. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123 Pt 6 (2000) 1174-1183
15. Bjartmar C., and Trapp B.D. Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol 14 3 (2001) 271-278
16. Bjartmar C., Kidd G., Mörk S., Rudick R., and Trapp B.D. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol. 48 6 (2000) 893-901
17. Bjartmar C., Kinkel R.P., Kidd G., Rudick R.A., and Trapp B.D. Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 57 7 (2001) 1248-1252
18. Black J.A., Liu S., Carrithers M., Carrithers L.M., and Waxman S.G. Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine. Ann Neurol. 62 1 (2007) 21-33
19. Black J.A., Liu S., Hains B.C., Saab C.Y., and Waxman S.G. Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE. Brain 129 Pt 12 (2006) 3196-3208
20. Bö L., Dawson T.M., Wesselingh S., Mörk S., Choi S., Kong P.A., et al. Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol 36 5 (1994) 778-786
21. Brady C.M., DasGupta R., Dalton C., Wiseman O.J., Berkley K.J., and Fowler C.J. An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Multiple Sclerosis 10 4 (2004) 425-433
22. Brand-Schieber E., and Werner P. Calcium channel blockers ameliorate disease in a mouse model of multiple sclerosis. Exp Neurol 189 1 (2004) 5-9
23. Brines M.L., Ghezzi P., Keenan S., Agnello D., de Lanerolle N.C., Cerami C., et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 97 19 (2000) 10526-10531
24. Brooks B.R. Managing amyotrophic lateral sclerosis: slowing disease progression and improving patient quality of life. Ann Neurol 65 Suppl 1 (2009) S17-23
25. Bruck W. Inflammatory demyelination is not central to the pathogenesis of multiple sclerosis. J Neurol 252 Suppl 5 (2005) v10-15
26. Bruck W., Bitsch A., Kolenda H., Bruck Y., Stiefel M., and Lassmann H. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 42 5 (1997) 783-793
27. Brunn A., Utermohlen O., Carstov M., Ruiz M.S., Miletic H., Schluter D., et al. CD4 T cells mediate axonal damage and spinal cord motor neuron apoptosis in murine p0106-125-induced experimental autoimmune neuritis. Am J Pathol 173 1 (2008) 93-105
28. Buemi M., Cavallaro E., Floccari F., Sturiale A., Aloisi C., Trimarchi M., et al. The pleiotropic effects of erythropoietin in the central nervous system. J Neuropathol Exp Neurol 62 3 (2003) 228-236
29. Cannella B., Pitt D., Capello E., and Raine C.S. Insulin-like growth factor-1 fails to enhance central nervous system myelin repair during autoimmune demyelination. Am J Pathol 157 3 (2000) 933-943
30. Centonze D., Bari M., Rossi S., Prosperetti C., Furlan R., Fezza F., et al. The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis. Brain 130 Pt 10 (2007) 2543-2553
31. Charcot J. Histologie de la sclerose en plaques. Gaz Hop Civ Mi 41 (1848) 554-566
32. Cheema S.S., Richards L., Murphy M., and Bartlett P.F. Leukemia inhibitory factor prevents the death of axotomised sensory neurons in the dorsal root ganglia of the neonatal rat. J Neurosci Res 37 2 (1994) 213-218
33. Cheema S.S., Richards L.J., Murphy M., and Bartlett P.F. Leukaemia inhibitory factor rescues motoneurones from axotomy-induced cell death. Neuroreport 5 8 (1994) 989-992
34. Chen H.S., and Lipton S.A. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem 97 6 (2006) 1611-1626
35. Clark A.J., Ware M.A., Yazer E., Murray T.J., and Lynch M.E. Patterns of cannabis use among patients with multiple sclerosis. Neurology 62 11 (2004) 2098-2100
36. Collin C., Davies P., Mutiboko I.K., Ratcliffe S., Group, and S. S. i. M. S. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 14 3 (2007) 290-296
37. Compston A. Remyelination of the central nervous system. Mult Scler 1 6 (1996) 388-392
38. Confavreux C., and Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 129 Pt 3 (2006) 606-616
39. Confavreux C., Vukusic S., Moreau T., and Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 343 20 (2000) 1430-1438
40. Costello F., Hodge W., Pan Y.I., Freedman M., and DeMeulemeester C. Differences in retinal nerve fiber layer atrophy between multiple sclerosis subtypes. J Neurol Sci 281 1-2 (2009) 74-79
41. Craner M.J., Damarjian T.G., Liu S., Hains B.C., Lo A.C., Black J.A., et al. Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia 49 2 (2005) 220-229
42. Craner M.J., Hains B.C., Lo A.C., Black J.A., and Waxman S.G. Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain 127 Pt 2 (2004) 294-303
43. 2+ exchanger. Proc Natl Acad Sci U S A 101 21 (2004) 8168-8173
44. Cross A.H., Misko T.P., Lin R.F., Hickey W.F., Trotter J.L., and Tilton R.G. Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. J Clin Invest 93 6 (1994) 2684-2690
45. Dandekar A.A., Wu G.F., Pewe L., and Perlman S. Axonal damage is T cell mediated and occurs concomitantly with demyelination in mice infected with a neurotropic coronavirus. J Virol 75 13 (2001) 6115-6120
46. De Stefano N., Matthews P., Filippi M., Agosta F., De Luca M., Bartolozzi M.L., et al. Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology 60 7 (2003) 1157-1162
47. De Stefano N., Matthews P.M., and Filippi M. Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology 60 (2003) 1157-1162
48. Diaz-Sanchez M., Williams K., DeLuca G.C., and Esiri M.M. Protein co-expression with axonal injury in multiple sclerosis plaques. Acta Neuropathol 111 4 (2006) 289-299
49. Diem R., Sättler M.B., Merkler D., Demmer I., Maier K., Stadelmann C., et al. Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 128 Pt 2 (2005) 375-385
50. Dutta R., McDonough J., Chang A., Swamy L., Siu A., Kidd G.J., et al. Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients. Brain 130 Pt 10 (2007) 2566-2576
51. Dutta R., McDonough J., Yin X., Peterson J., Chang A., Torres T., et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59 3 (2006) 478-489
52. Ehrenreich H., Fischer B., Norra C., Schellenberger F., Stender N., Stiefel M., et al. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 130 Pt 10 (2007) 2577-2588
53. Evangelou N., Esiri M.M., Smith S., Palace J., and Matthews P.M. Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 47 3 (2000) 391-395
54. Fazekas F., Soelberg-Sorensen P., Comi G., and Filippi M. MRI to monitor treatment efficacy in multiple sclerosis. J Neuroimaging 17 Suppl 1 (2007) 50S-55S
55. Fenyk-Melody J.E., Garrison A.E., Brunnert S.R., Weidner J.R., Shen F., Shelton B.A., et al. Experimental autoimmune encephalomyelitis is exacerbated in mice lacking the NOS2 gene. J Immunol 160 6 (1998) 2940-2946
56. Ferguson B., Matyszak M.K., Esiri M.M., and Perry V.H. Axonal damage in acute multiple sclerosis lesions. Brain 120 Pt 3 (1997) 393-399
57. Fern R., Ransom B.R., and Waxman S.G. Voltage-gated calcium channels in CNS white matter: role in anoxic injury. J Neurophysiol 74 1 (1995) 369-377
58. Filippi M., Bozzali M., Rovaris M., Gonen O., Kesavadas C., Ghezzi A., et al. Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 126 Pt 2 (2003) 433-437
59. Fisher J.B., Jacobs D.A., Markowitz C.E., Galetta S.L., Volpe N.J., Nano-Schiavi M.L., et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmol 113 (2006) 324-332
60. Fischer J.S., Rudick R.A., Cutter G.R., and Reingold S.C. The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force. Multiple Sclerosis 5 4 (1999) 244-250
61. Fisniku L., Chard D., Jackson J., Anderson V., Altmann D., Miszkiel K., et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 64 3 (2008) 247-254
62. Frank J.A., Richert N., Lewis B., Bash C., Howard T., Civil R., et al. A pilot study of recombinant insulin-like growth factor-1 in seven multiple sclerosis patients. Multiple Sclerosis 8 1 (2002) 24-29
63. Fraser C., Klistorner A., Graham S., Garrick R., Billson F., and Grigg J. Multifocal visual evoked potential latency analysis: predicting progression to multiple sclerosis. Arch Neurol 63 6 (2006) 847-850
64. Frohman E.M., Costello F., Stuve O., Calabresi P., Miller D.H., Hickman S.J., et al. Modeling axonal degeneration within the anterior visual system: implications for demonstrating neuroprotection in multiple sclerosis. Arch Neurol 65 1 (2008) 26-35
65. Fujiwara M., and Egashira N. New perspectives in the studies on endocannabinoid and cannabis: abnormal behaviors associate with CB1 cannabinoid receptor and development of therapeutic application. J Pharmacol Sci 96 4 (2004) 362-366
66. Garthwaite G., Goodwin D.A., Neale S., Riddall D., and Garthwaite J. Soluble guanylyl cyclase activator YC-1 protects white matter axons from nitric oxide toxicity and metabolic stress, probably through Na(+) channel inhibition. Mol Pharmacol 61 1 (2002) 97-104
67. Gartner D., Hoff H., Gimsa U., Burmester G.R., and Brunner-Weinzierl M.C. CD25 regulatory T cells determine secondary but not primary remission in EAE: impact on long-term disease progression. J Neuroimmunol 172 1-2 (2006) 73-84
68. Genoud S., Maricic I., Kumar V., and Gage F.H. Targeted expression of IGF-1 in the central nervous system fails to protect mice from experimental autoimmune encephalomyelitis. J Neuroimmunol 168 1-2 (2005) 40-45
69. Golde S., Chandran S., Brown G.C., and Compston A. Different pathways for iNOS-mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression. J Neurochem 82 2 (2002) 269-282
70. PRISMS Study Group. PRISMS-4: long-term efficacy of interferon-beta-1a in relapsing MS. Neurology 56 12 (2001) 1628-1636
71. SPECTRIMS Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology 56 11 (2001) 1496-1504
72. Hagg T., Varon S., and Louis J.C. Ciliary neurotrophic factor (CNTF) promotes low-affinity nerve growth factor receptor and CD4 expression by rat CNS microglia. J Neuroimmunol 48 2 (1993) 177-187
73. Halliday A.M., McDonald W.I., and Mushin J. Delayed visual evoked response in optic neuritis. Lancet 1 7758 (1972) 982-985
74. Hammarberg H., Lidman O., Lundberg C., Eltayeb S.Y., Gielen A.W., Muhallab S., et al. Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells. J Neurosci 20 14 (2000) 5283-5291
75. Hassen G.W., Feliberti J., Kesner L., Stracher A., and Mokhtarian F. Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis. Brain Res 1236 (2008) 206-215
76. Hauser S.L., and Oksenberg J.R. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52 1 (2006) 61-76
77. Hemmer B., and Hartung H.P. Toward the development of rational therapies in multiple sclerosis: what is on the horizon?. Ann Neurol 62 4 (2007) 314-326
78. Hendriks J.J., Teunissen C.E., de Vries H.E., and Dijkstra C.D. Macrophages and neurodegeneration. Brain Res Brain Res Rev 48 2 (2005) 185-195
79. Herrero-Herranz E., Pardo L.A., Gold R., and Linker R.A. Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: implications for multiple sclerosis. Neurobiol Dis 30 2 (2008) 162-173
80. Hickman S.J., Kapoor R., Jones S.J., Altmann D.R., Plant G.T., and Miller D.H. Corticosteroids do not prevent optic nerve atrophy following optic neuritis. J Neurol Neurosurg Psychiatry 74 8 (2003) 1139-1141
81. Hickman S.J., Toosy A.T., Jones S.J., Altmann D.R., Miszkiel K.A., MacManus D.G., et al. A serial MRI study following optic nerve mean area in acute optic neuritis. Brain 127 Pt 11 (2004) 2498-2505
82. Hickman S.J., Toosy A.T., Jones S.J., Altmann D.R., Miszkiel K.A., MacManus D.G., et al. Serial magnetization transfer imaging in acute optic neuritis. Brain 127 Pt 3 (2004) 692-700
83. Hickman S.J., Wheeler-Kingshott C.A., Jones S.J., Miszkiel K.A., Barker G.J., Plant G.T., et al. Optic nerve diffusion measurement from diffusion-weighted imaging in optic neuritis. AJNR Am J Neuroradiol 26 4 (2005) 951-956
84. Hogg N. The biochemistry and physiology of S-nitrosothiols. Annu Rev Pharmacol Toxicol 42 (2002) 585-600
85. Howlett A.C. The cannabinoid receptors. Prostaglandins Other Lipid Mediat 68-69 (2002) 619-631
86. Hughes R.A., Sendtner M., and Thoenen H. Members of several gene families influence survival of rat motoneurons in vitro and in vivo. J Neurosci Res 36 6 (1993) 663-671
87. 2+ channels in anoxic injury of spinal cord white matter. Brain Res 817 1-2 (1999) 84-92
88. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 45 7 (1995) 1277-1285
89. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43 4 (1993) 655-661
90. Jacobs L.D., Beck R.W., Simon J.H., Kinkel R.P., Brownscheidle C.M., Murray T.J., et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343 13 (2000) 898-904
91. Kalkers N.F., Barkhof F., Bergers E., van Schijndel R., and Polman C.H. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Multiple Sclerosis 8 6 (2002) 532-533
92. Kalkers N.F., Bergers E., Castelijns J.A., van Walderveen M.A., Bot J.C., Adèr H.J., et al. Optimizing the association between disability and biological markers in MS. Neurology 57 7 (2001) 1253-1258
93. Kapoor R. Neuroprotection in multiple sclerosis: therapeutic strategies and clinical trial design. Curr Opin Neurol 19 3 (2006) 255-259
94. Kapoor R. Sodium channel blockers and neuroprotection in multiple sclerosis using lamotrigine. J Neurol Sci 274 1-2 (2008) 54-56
95. Kappos L., Polman C., Pozzilli C., Thompson A., Beckmann K., Dahlke F., et al. Final analysis of the European multicenter trial on IFNbeta-1b in secondary-progressive MS. Neurology 57 11 (2001) 1969-1975
96. Killestein J., Kalkers N.F., and Polman C.H. Glutamate inhibition in MS: the neuroprotective properties of riluzole. J Neurol Sci 233 1-2 (2005) 113-115
97. Klistorner A., Arvind H., Nguyen T., Garrick R., Paine M., Graham S., et al. Axonal loss and myelin in early ON loss in postacute optic neuritis. Ann Neurol 64 3 (2008) 325-331
98. Klistorner A., Fraser C., Garrick R., Graham S., and Arvind H. Correlation between full-field and multifocal VEPs in optic neuritis. Doc Ophthalmol 116 1 (2008) 19-27
99. Kolbe S., Chapman C., Nguyen T., Bajraszewski C., Johnston L., Kean M., et al. Optic nerve diffusion changes and atrophy jointly predict visual dysfunction after optic neuritis. Neuroimage 45 3 (2009) 679-686
100. Kornek B., Storch M.K., Bauer J., Djamshidian A., Weissert R., Wallstroem E., et al. Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain 124 Pt 6 (2001) 1114-1124
101. Kornek B., Storch M.K., Weissert R., Wallstroem E., Stefferl A., Olsson T., et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157 1 (2000) 267-276
102. Krady J.K., Lin H.W., Liberto C.M., Basu A., Kremlev S.G., and Levison S.W. Ciliary neurotrophic factor and interleukin-6 differentially activate microglia. J Neurosci Res 86 7 (2008) 1538-1547
103. Kreitzer A.C., and Regehr W.G. Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J Neurosci 21 20 (2001) RC174
104. Kurtzke J. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33 (1983) 1444-1452
105. Kutzelnigg A., Lucchinetti C.F., Stadelmann C., Brück W., Rauschka H., Bergmann M., et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128 Pt 11 (2005) 2705-2712
106. Lassmann H. Axonal injury in multiple sclerosis. J Neurol Neurosurg Psychiatry 74 6 (2003) 695-697
107. Lassmann H., Brück W., and Lucchinetti C.F. The immunopathology of multiple sclerosis: an overview. Brain Pathol 17 2 (2007) 210-218
108. Laursen L.S., and Ffrench-Constant C. Adhesion molecules in the regulation of CNS myelination. Neuron Glia Biol 3 4 (2007) 367-375
109. Li W., Maeda Y., Yuan R.R., Elkabes S., Cook S., and Dowling P. Beneficial effect of erythropoietin on experimental allergic encephalomyelitis. Ann Neurol 56 6 (2004) 767-777
110. Li W., Quigley L., Yao D.L., Hudson L.D., Brenner M., Zhang B.J., et al. Chronic relapsing experimental autoimmune encephalomyelitis: effects of insulin-like growth factor-I treatment on clinical deficits, lesion severity, glial responses, and blood brain barrier defects. J Neuropathol Exp Neurol 57 5 (1998) 426-438
111. Ligresti A., Cascio M.G., Pryce G., Kulasegram S., Beletskaya I., De Petrocellis L., et al. New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis. Br J Pharmacol 147 1 (2006) 83-91
112. Liu X., Linnington C., Webster H.D., Lassmann S., Yao D.L., Hudson L.D., et al. Insulin-like growth factor-I treatment reduces immune cell responses in acute non-demyelinative experimental autoimmune encephalomyelitis. J Neurosci Res 47 5 (1997) 531-538
113. Lo A.C., Saab C.Y., Black J.A., and Waxman S.G. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J Neurophysiol 90 5 (2003) 3566-3571
114. Lovas G., Szilágyi N., Majtényi K., Palkovits M., and Komoly S. Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 123 Pt 2 (2000) 308-317
115. Lucchinetti C., Bruck W., Parisi J., Scheithauer B., Rodriguez M., and Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47 6 (2000) 707-717
116. Maier O., De Jonge J., Nomden A., Hoekstra D., and Baron W. Lovastatin induces the formation of abnormal myelin-like membrane sheets in primary oligodendrocytes. Glia 57 4 (2009) 402-413
117. Matute C., Alberdi E., Ibarretxe G., and Sanchez-Gomez M.V. Excitotoxicity in glial cells. Eur J Pharmacol 447 2-3 (2002) 239-246
118. McMorris F.A., and McKinnon R.D. Regulation of oligodendrocyte development and CNS myelination by growth factors: prospects for therapy of demyelinating disease. Brain Pathol 6 3 (1996) 313-329
119. Medana I., Martinic M.A., Wekerle H., and Neumann H. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am J Pathol 159 3 (2001) 809-815
120. Miller D., Barkhof F., Frank J.A., Parker G.J., and Thompson A. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 125 Pt 8 (2002) 1676-1695
121. Miller D., Barkhof F., Montalban X., Thompson A., and Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 4 5 (2005) 281-288
122. Miller D.H., Thompson A.J., and Filippi M. Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis. J Neurol 250 12 (2003) 1407-1419
123. Moncada S., and Bolaños J.P. Nitric oxide, cell bioenergetics and neurodegeneration. J Neurochem 97 6 (2006) 1676-1689
124. Naismith R.T., Xu J., Tutlam N.T., Snyder A., Benzinger T., Shimony J., et al. Disability in optic neuritis correlates with diffusion tensor-derived directional diffusivities. Neurology (2008)
125. Neuhaus O., and Hartung H.P. Evaluation of atorvastatin and simvastatin for treatment of multiple sclerosis. Expert Rev Neurother 7 5 (2007) 547-556
126. Neumann H., Medana I.M., Bauer J., and Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci 25 6 (2002) 313-319
127. Noval S., Contreras I., Rebolleda G., and Munoz-Negrete F.J. Optical coherence tomography versus automated perimetry for follow-up of optic neuritis. Acta Ophthalmol Scan 84 (2006) 790-794
128. Ortega-Gutiérrez S., Molina-Holgado E., and Guaza C. Effect of anandamide uptake inhibition in the production of nitric oxide and in the release of cytokines in astrocyte cultures. Glia 52 2 (2005) 163-168
129. Ouardouz M., Coderre E., Basak A., Chen A., Zamponi G.W., Hameed S., et al. Glutamate receptors on myelinated spinal cord axons: I. GluR6 kainate receptors. Ann Neurol 65 2 (2009) 151-159
130. Ouardouz M., Coderre E., Zamponi G.W., Hameed S., Yin X., Trapp B., et al. Glutamate receptors on myelinated spinal cord axons: II. AMPA and GluR5 receptors. Ann Neurol 65 2 (2009) 160-166
131. 2+ stores during ischaemia in rat spinal cord white matter. J Physiol (Lond) 577 Pt 1 (2006) 191-204
132. 2+ channel activation of ryanodine receptors. Neuron 40 1 (2003) 53-63
133. Ozdinler P.H., and Macklis J.D. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci 9 11 (2006) 1371-1381
134. Ozog M.A., Modha G., Church J., Reilly R., and Naus C.C. Co-administration of ciliary neurotrophic factor with its soluble receptor protects against neuronal death and enhances neurite outgrowth. J Biol Chem 283 10 (2008) 6546-6560
135. Paintlia A.S., Paintlia M.K., Singh I., Skoff R.B., and Singh A.K. Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis. Glia 57 2 (2009) 182-193
136. Paty D.W., Li D.K., Group, and U. M. M. S. G. a. I. M. S. S. Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. 1993 [classical article]. Neurology 57 12 Suppl 5 (2001) S10-S15
137. Pitt D., Werner P., and Raine C.S. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 6 1 (2000) 67-70
138. Plant G.T. Optic neuritis and multiple sclerosis. Curr Opin Neurol 21 1 (2008) 16-21
139. Polman C.H., O'Connor P.W., Havrdova E., Hutchinson M., Kappos L., Miller D.H., et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354 9 (2006) 899-910
140. Polman C.H., Reingold S.C., Edan G., Filippi M., Hartung H.P., Kappos L., et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 58 6 (2005) 840-846
141. Poser C.M., Paty D.W., Scheinberg L., McDonald W.I., Davis F.A., Ebers G.C., et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13 3 (1983) 227-231
142. Pryce G., Ahmed Z., Hankey D.J., Jackson S.J., Croxford J.L., Pocock J.M., et al. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126 Pt 10 (2003) 2191-2202
143. Pryce G., and Baker D. Emerging properties of cannabinoid medicines in management of multiple sclerosis. Trends Neurosci 28 5 (2005) 272-276
144. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 352 9139 (1998) 1498-1504
145. Rao A.B., Richert N., Howard T., Lewis B.K., Bash C.N., McFarland H.F., et al. Methylprednisolone effect on brain volume and enhancing lesions in MS before and during IFNbeta-1b. Neurology 59 5 (2002) 688-694
146. Rizvi S.A., and Agius M.A. Current approved options for treating patients with multiple sclerosis. Neurology 63 12 Suppl 6 (2004) S8-14
147. Rog D.J., Nurmikko T.J., Friede T., and Young C.A. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 65 6 (2005) 812-819
148. Sango K., Yanagisawa H., Komuta Y., Si Y., and Kawano H. Neuroprotective properties of ciliary neurotrophic factor for cultured adult rat dorsal root ganglion neurons. Histochem Cell Biol 130 4 (2008) 669-679
149. Scherer S. Axonal pathology in demyelinating diseases. Ann Neurol 45 1 (1999) 6-7
150. Sendtner M., Götz R., Holtmann B., Escary J.L., Masu Y., Carroll P., et al. Cryptic physiological trophic support of motoneurons by LIF revealed by double gene targeting of CNTF and LIF. Curr Biol 6 6 (1996) 686-694
151. Sendtner M., Kreutzberg G.W., and Thoenen H. Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy. Nature 345 6274 (1990) 440-441
152. Sepulcre J., Murie-Fernandez M., Salinas-Alaman A., Garcia-Layana A., Bejarano B., and Villoslada P. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology 68 18 (2007) 1488-1494
153. Singh V.K., Mehrotra S., Narayan P., Pandey C.M., and Agarwal S.S. Modulation of autoimmune diseases by nitric oxide. Immunol Res 22 1 (2000) 1-19
154. Smith K.J., and Lassmann H. The role of nitric oxide in multiple sclerosis. Lancet neurology 1 4 (2002) 232-241
155. Smith T., Groom A., Zhu B., and Turski L. Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 6 1 (2000) 62-66
156. Song S.K., Sun S.W., Ju W.K., Lin S.J., Cross A.H., and Neufeld A.H. Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 20 3 (2003) 1714-1722
157. Sorensen P., Frederiksen J., and Lycke L. Does simvastatin antagonize the effect of interferon-beta? Interim safety analysis of ongoing SIMCOMBIN study. Mult Scler Suppl 2 (2007) Abstract 85
158. Sriram S., and Steiner I. Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann Neurol 58 6 (2005) 939-945
159. Steinman L., and Zamvil S.S. How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann Neurol 60 1 (2006) 12-21
160. Storch M.K., Stefferl A., Brehm U., Weissert R., Wallström E., Kerschensteiner M., et al. Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol 8 4 (1998) 681-694
161. Stys P.K. General mechanisms of axonal damage and its prevention. J Neurol Sci 233 1-2 (2005) 3-13
162. Stys P.K., Ransom B.R., Waxman S.G., and Davis P.K. Role of extracellular calcium in anoxic injury of mammalian central white matter. Proc Natl Acad Sci U S A 87 11 (1990) 4212-4216
163. Stys P.K., Waxman S.G., and Ransom B.R. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger. J Neurosci 12 2 (1992) 430-439
164. Tekkok S.B., and Goldberg M.P. Ampa/kainate receptor activation mediates hypoxic oligodendrocyte death and axonal injury in cerebral white matter. J Neurosci 21 12 (2001) 4237-4248
165. Trapp B., and Stys P. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurology 8 3 (2009) 280-291
166. Trapp B.D., Peterson J., Ransohoff R.M., Rudick R., Mork S., and Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338 5 (1998) 278-285
167. Trip S.A., Schlottmann P.G., Jones S.J., Altmann D.R., Garway-Heath D.F., Thompson A.J., et al. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol 58 3 (2005) 383-391
168. Trip S.A., Schlottmann P.G., Jones S.J., Li W.Y., Garway-Heath D.F., Thompson A.J., et al. Optic nerve atrophy and retinal nerve fibre layer thinning following optic neuritis: evidence that axonal loss is a substrate of MRI-detected atrophy. Neuroimage 31 1 (2006) 286-293
169. Trip S.A., Wheeler-Kingshott C., Jones S.J., Li W.Y., Barker G.J., Thompson A.J., et al. Optic nerve diffusion tensor imaging in optic neuritis. Neuroimage 30 2 (2006) 498-505
170. Trojano M., Pellegrini F., Fuiani A., Paolicelli D., Zipoli V., Zimatore G.B., et al. New natural history of interferon-beta-treated relapsing multiple sclerosis. Ann Neurol 61 4 (2007) 300-306
171. Tubridy N., Ader H.J., Barkhof F., Thompson A., and Miller D.H. Exploratory treatment trials in multiple sclerosis using MRI: sample size calculations for relapsing-remitting and secondary progressive subgroups using placebo controlled parallel groups. J Neurol Neurosurg Psychiatr 64 1 (1998) 50-55
172. van Walderveen M.A., Barkhof F., Tas M.W., Polman C., Frequin S.T., Hommes O.R., et al. Patterns of brain magnetic resonance abnormalities on T2-weighted spin echo images in clinical subgroups of multiple sclerosis: a large cross-sectional study. Eur J Neurol 40 (1998) 91-98
173. van Walderveen M.A., Kamphorst W., Scheltens P., van Waesberghe J.H., Ravid R., Valk J., et al. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 50 5 (1998) 1282-1288
174. Vanderlocht J., Hellings N., Hendriks J.J., and Stinissen P. Current trends in multiple sclerosis research: an update on pathogenic concepts. Acta Neurol Belg 106 4 (2006) 180-190
175. Vollmer T., Key L., Durkalski V., Tyor W., Corboy J., Markovic-Plese S., et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 363 9421 (2004) 1607-1608
176. Wallström E., Diener P., Ljungdahl A., Khademi M., Nilsson C.G., and Olsson T. Memantine abrogates neurological deficits, but not CNS inflammation, in Lewis rat experimental autoimmune encephalomyelitis. J Neurol Sci 137 2 (1996) 89-96
177. Walters R.J., Fox N.C., Crum W.R., Taube D., and Thomas D.J. Haemodialysis and cerebral oedema. Nephron 87 2 (2001) 143-147
178. Waxman S.G. Demyelinating diseases-new pathological insights, new therapeutic targets. N Engl J Med 338 5 (1998) 323-325
179. Waxman S.G. Acquired channelopathies in nerve injury and MS. Neurology 56 12 (2001) 1621-1627
180. Wekerle H. Lessons from multiple sclerosis: models, concepts, observations. Ann Rheum Dis 67 Suppl 3 (2008) iii56-iii60
181. Wilkins A., Chandran S., and Compston A. A role for oligodendrocyte-derived IGF-1 in trophic support of cortical neurons. Glia 36 1 (2001) 48-57
182. Wilkins A., and Compston A. Trophic factors attenuate nitric oxide mediated neuronal and axonal injury in vitro: roles and interactions of mitogen-activated protein kinase signalling pathways. J Neurochem 92 6 (2005) 1487-1496
183. Wilkins A., Majed H., Layfield R., Compston A., and Chandran S. Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J Neurosci 23 12 (2003) 4967-4974
184. Wu Q., Butzkueven H., Gresle M., Kirchhoff F., Friedhuber A., Yang Q., et al. MR diffusion changes correlate with ultra-structurally defined axonal degeneration in murine optic nerve. Neuroimage 37 4 (2007) 1138-1147
185. Wujek J.R., Bjartmar C., Richer E., Ransohoff R.M., Yu M., Tuohy V.K., et al. Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J Neuropathol Exp Neurol 61 1 (2002) 23-32
186. Yao D.L., Liu X., Hudson L.D., and Webster H.D. Insulin-like growth factor-I given subcutaneously reduces clinical deficits, decreases lesion severity and upregulates synthesis of myelin proteins in experimental autoimmune encephalomyelitis. Life Sci 58 16 (1996) 1301-1306
187. Yin Q.W., Johnson J., Prevette D., and Oppenheim R.W. Cell death of spinal motoneurons in the chick embryo following deafferentation: rescue effects of tissue extracts, soluble proteins, and neurotrophic agents. J Neurosci 14 12 (1994) 7629-7640
188. Youssef S., Stüve O., Patarroyo J.C., Ruiz P.J., Radosevich J.L., Hur E.M., et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420 6911 (2002) 78-84
189. Zamvil S., Nelson P., Trotter J., Mitchell D., Knobler R., Fritz R., et al. T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. Nature 317 6035 (1985) 355-358
190. Ziskin J.L., Nishiyama A., Rubio M., Fukaya M., and Bergles D.E. Vesicular release of glutamate from unmyelinated axons in white matter. Nat Neurosci 10 3 (2007) 321-330