Prevention of acute autoimmune encephalomyelitis and abrogation of relapses in murine models of multiple sclerosis by the protease inhibitor D-penicillamine.
The in vitro activity of gelatinase B, an enzyme whose appearance in the cerebrospinal fluid is associated with inflammatory diseases of the central nervous system, was dose-dependently inhibited by the antirheumatic D-penicillamine. Inhibition of gelatinase B in electrophoretically pure preparations and in cell culture supernatants and human body fluids was obtained at dosages reached in the circulation of patients treated with a peroral dosis of 750 mg D-penicillamine per day. In mice, developing acute demyelination, D-penicillamine significantly reduced the mortality and morbidity rates of experimental allergic encephalomyelitis (EAE). In chronic relapsing EAE in Biozzi AB/H mice, an animal model for relapses in multiple sclerosis (MS), it attenuated the exacerbations, even when the treatment was started after the primary full-blown disease had developed. We infer protease inhibition as the mechanism of action of D-penicillamine and suggest that its use may be effective as peroral treatment for MS.
Norga
K
K
Laboratory of Molecular Immunology, University of Leuven, Belgium.
Paemen
L
L
Masure
S
S
Dillen
C
C
Heremans
H
H
Billiau
A
A
Carton
H
H
Cuzner
L
L
Olsson
T
T
Van Damme
J
J
D000208:Acute Disease; D000818:Animals; D015152:Blotting, Northern; D002908:Chronic Disease; D017364:Collagenases / Q000134:cerebrospinal fluid; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009103:Multiple Sclerosis / Q000517:prevention & control*; D010396:Penicillamine / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012008:Recurrence
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D017364:Collagenases; D020780:Matrix Metalloproteinase 9; D010396:Penicillamine