PREVENTION AND TREATMENT OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITISBY CNI-1493, A MACROPHAGE-DEACTIVATING AGENT

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are characterized by episodic neurologic dysf unction, perivascular mononuclear cell inflammation occurring mainly i n white matter, and demyelination. Strong circumstantial evidence supp orts the conclusion that macrophage activation and local production of proinflammatory cytokines are necessary for disease induction and les ion formation. We now report that CNI-1493, a small m.w, compound, whi ch inhibits macrophage activation and subsequent proinflammatory cytok ine production, suppresses EAE induced in the genetically susceptible SJL/J mouse. Treatment with 5 mg/kg/day completely suppressed mild dis ease (clinical index of 1.6 +/- 0.5 in the untreated group as compared with 0.0 +/- 0.0 for the treated group) and significantly reduced acu te disease (clinical index of 4.3 +/- 0.7 in the untreated group as co mpared with 0.5 +/- 0.3 for the treated group). Suppression of clinica l manifestations of the disease correlated with a significant decrease in histopathology and proinflammatory cytokine expression at the lesi on site, Moreover, drug treatment during the chronic phase resulted in amelioration of clinical signs. The data presented here should prove useful in developing navel chemotherapeutic approaches for the treatme nt of MS.