PMID- 9667591
OWN - NLM
STAT- MEDLINE
DCOM- 19980722
LR  - 20131121
IS  - 0364-5134 (Print)
IS  - 0364-5134 (Linking)
VI  - 44
IP  - 1
DP  - 1998 Jul
TI  - Effective treatment of models of multiple sclerosis by matrix metalloproteinase 
      inhibitors.
PG  - 35-46
AB  - The proinflammatory Th1 cytokine, tumor necrosis factor-alpha (TNF alpha), 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 TNF alpha-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 TNF alpha 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 TNF alpha 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 TNF alpha shedding by human 
      myelin-autoreactive T cells.
FAU - Liedtke, W
AU  - Liedtke W
AD  - Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
FAU - Cannella, B
AU  - Cannella B
FAU - Mazzaccaro, R J
AU  - Mazzaccaro RJ
FAU - Clements, J M
AU  - Clements JM
FAU - Miller, K M
AU  - Miller KM
FAU - Wucherpfennig, K W
AU  - Wucherpfennig KW
FAU - Gearing, A J
AU  - Gearing AJ
FAU - Raine, C S
AU  - Raine CS
LA  - eng
GR  - NS 07098/NS/NINDS NIH HHS/United States
GR  - NS 08952/NS/NINDS NIH HHS/United States
GR  - NS 11920/NS/NINDS NIH HHS/United States
GR  - etc.
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Ann Neurol
JT  - Annals of neurology
JID - 7707449
RN  - 0 (BB 1101)
RN  - 0 (BB 1268)
RN  - 0 (BB 2275)
RN  - 0 (Benzyl Compounds)
RN  - 0 (Cytokines)
RN  - 0 (Drug Combinations)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Organic Chemicals)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Succinates)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 63231-63-0 (RNA)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - SD6QCT3TSU (Pentoxifylline)
SB  - IM
MH  - Animals
MH  - Astrocytes/chemistry
MH  - Autoimmune Diseases/drug therapy/pathology
MH  - Base Sequence
MH  - Benzyl Compounds
MH  - Chi-Square Distribution
MH  - Clone Cells
MH  - Cytokines/analysis/genetics
MH  - Demyelinating Diseases/pathology/prevention & control
MH  - Dexamethasone/pharmacology/*therapeutic use
MH  - Down-Regulation
MH  - Drug Combinations
MH  - Encephalitis/*drug therapy/pathology
MH  - Gene Expression Regulation/drug effects
MH  - Glial Fibrillary Acidic Protein/analysis
MH  - Humans
MH  - Hydroxamic Acids/*therapeutic use
MH  - Immunohistochemistry
MH  - Metalloendopeptidases/*antagonists & inhibitors
MH  - Mice
MH  - Microglia/chemistry
MH  - Microscopy, Electron
MH  - Multiple Sclerosis/*drug therapy/pathology
MH  - Optic Nerve/ultrastructure
MH  - Organic Chemicals
MH  - Pentoxifylline/pharmacology/*therapeutic use
MH  - Protease Inhibitors/pharmacology/*therapeutic use
MH  - RNA/analysis
MH  - Recurrence
MH  - Spinal Cord/ultrastructure
MH  - Statistics, Nonparametric
MH  - Succinates
MH  - Tumor Necrosis Factor-alpha/drug effects
MH  - Up-Regulation
EDAT- 1998/07/17 00:00
MHDA- 1998/07/17 00:01
CRDT- 1998/07/17 00:00
PHST- 1998/07/17 00:00 [pubmed]
PHST- 1998/07/17 00:01 [medline]
PHST- 1998/07/17 00:00 [entrez]
AID - 10.1002/ana.410440110 [doi]
PST - ppublish
SO  - Ann Neurol. 1998 Jul;44(1):35-46. doi: 10.1002/ana.410440110.