Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors

Wolfgang Liedtke, Barbara Cannella, Richard J. Mazzaccaro, John M. Clements, Karen M. Miller, Kai W. Wucherpfennig, Andrew J H Gearing, Cedric S. Raine

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

The proinflammatory Th1 cytokine, tumor necrosis factor-α (TNFα), the cell death signaling molecule FasL, and several extracellular matrix degrading metalloproteinases have been implicated in the pathogenesis of multiple sclerosis (MS). The latter enzymes, as well as TNFα-converting enzyme and FasL-converting enzyme, can be blocked by matrix metalloproteinase inhibitors (MMPIs). In this study, we show that a potent MMPI was clinically effective in an animal model for MS, experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse. Efficacy was remarkable, as indicated by blocking and reversal of acute disease and reduced number of relapses and diminished mean cumulative disease score in chronic relapsing animals. Also, demyelination and glial scarring were significantly decreased in MMPI-treated mice with chronic relapsing EAE, as was central nervous system gene expression for TNFα and fasL. It is interesting that expression of the beneficial cytokine interleukin-4 (IL-4) was increased, and IL-4 was expressed on glial cells. The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNFα shedding and cytotoxicity of myelin-autoreactive human cytotoxic CD4+ T-cell clones. This is the first report to show a positive effect by MMPIs on chronic relapsing EAE, its central nervous system cytokine profile, and on TNFα shedding by human myelin-autoreactive T cells.

Original languageEnglish (US)
Pages (from-to)35-46
Number of pages12
JournalAnnals of Neurology
Volume44
Issue number1
DOIs
StatePublished - Jul 1998

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Matrix Metalloproteinase Inhibitors
Multiple Sclerosis
Autoimmune Experimental Encephalomyelitis
Tumor Necrosis Factor-alpha
Cytokines
Myelin Sheath
Neuroglia
Interleukin-4
Enzymes
Central Nervous System
T-Lymphocytes
Demyelinating Diseases
Acute Disease
Matrix Metalloproteinases
Cicatrix
Extracellular Matrix
Cell Death
Animal Models
Clone Cells
Gene Expression

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Liedtke, W., Cannella, B., Mazzaccaro, R. J., Clements, J. M., Miller, K. M., Wucherpfennig, K. W., ... Raine, C. S. (1998). Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors. Annals of Neurology, 44(1), 35-46. https://doi.org/10.1002/ana.410440110

Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors. / Liedtke, Wolfgang; Cannella, Barbara; Mazzaccaro, Richard J.; Clements, John M.; Miller, Karen M.; Wucherpfennig, Kai W.; Gearing, Andrew J H; Raine, Cedric S.

In: Annals of Neurology, Vol. 44, No. 1, 07.1998, p. 35-46.

Research output: Contribution to journalArticle

Liedtke, W, Cannella, B, Mazzaccaro, RJ, Clements, JM, Miller, KM, Wucherpfennig, KW, Gearing, AJH & Raine, CS 1998, 'Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors', Annals of Neurology, vol. 44, no. 1, pp. 35-46. https://doi.org/10.1002/ana.410440110
Liedtke W, Cannella B, Mazzaccaro RJ, Clements JM, Miller KM, Wucherpfennig KW et al. Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors. Annals of Neurology. 1998 Jul;44(1):35-46. https://doi.org/10.1002/ana.410440110
Liedtke, Wolfgang ; Cannella, Barbara ; Mazzaccaro, Richard J. ; Clements, John M. ; Miller, Karen M. ; Wucherpfennig, Kai W. ; Gearing, Andrew J H ; Raine, Cedric S. / Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors. In: Annals of Neurology. 1998 ; Vol. 44, No. 1. pp. 35-46.
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