Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases.
Gelatinases, belonging to the matrix metalloproteases, contribute to tissue destruction in inflammatory demyelinating disorders of the central nervous system such as multiple sclerosis. We used experimental autoimmune encephalomyelitis (EAE) as an animal model to evaluate the effect of a hydroxamate matrix metalloprotease inhibitor (GM 6001) on inflammatory demyelination. A single dose of the inhibitor, given intraperitoneally, provided sufficient levels in the cerebrospinal fluid of animals with EAE to induce at least a partial inhibition of the gelatinase activity in the cerebrospinal fluid. When administered daily either from the time of disease induction or from the onset of clinical signs, GM 6001 suppressed the development or reversed clinical EAE in a dose-dependent way, respectively. Animals returned to the same clinical course as the nontreated group after cessation of treatment. Animals treated from the onset of clinical signs had normal permeability of the blood-brain barrier, compared with the enhanced permeability in nontreated animals. These results indicate that matrix metalloprotease inhibition can reverse ongoing EAE. This effect appears to be mediated mainly through restoration of the damaged blood-brain barrier in the inflammatory phase of the disease, since, the degree of demyelination and inflammation did not differ between the treatment groups.
Gijbels
K
K
Department of Neurology and Neurological Sciences, Stanford University Medical School, California 94305.
Galardy
R E
RE
Steinman
L
L
D000818:Animals; D001327:Autoimmune Diseases / Q000628:therapy*; D001812:Blood-Brain Barrier; D003711:Demyelinating Diseases / Q000628:therapy*; D004151:Dipeptides / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004679:Encephalomyelitis / Q000628:therapy*; D005260:Female; D018093:Gelatinases / Q000134:cerebrospinal fluid; D007274:Injections, Intraperitoneal; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008815:Mice, Inbred Strains; D010539:Permeability
D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D018093:Gelatinases; D008666:Metalloendopeptidases