REVERSAL OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS WITH A HYDROXAMATE INHIBITOR OF MATRIX METALLOPROTEASES

Gelatinases, belonging to the matrix metalloproteases, contribute to t issue destruction in inflammatory demyelinating disorders of the centr al nervous system such as multiple sclerosis. We used experimental aut oimmune encephalomyelitis (EAE) as an animal model to evaluate the eff ect of a hydroxamate matrix metalloprotease inhibitor (GM 6001) on inf lammatory demyelination. A single dose of the inhibitor, given intrape ritoneally, provided sufficient levels in the cerebrospinal fluid of a nimals with EAE to induce at least a partial inhibition of the gelatin ase activity in the cerebrospinal fluid. When administered daily eithe r from the time of disease induction or from the onset of clinical sig ns, GM 6001 suppressed the development or reversed clinical EAE in a d ose-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 th e blood-brain barrier, compared with the enhanced permeability in nont reated animals. These results indicate that matrix metalloprotease inh ibition can reverse ongoing EAE. This effect appears to be mediated ma inly through restoration of the damaged blood-brain barrier in the inf lammatory phase of the disease, since the degree of demyelination and inflammation did not differ between the treatment groups.