THERAPEUTIC ACTIVITY OF MALONONITRILAMIDES (MNA-279 AND MNA-715) ON ACUTE AND CHRONIC, RELAPSING, EXPERIMENTAL, ALLERGIC ENCEPHALOMYELITIS (EAE)

Due to their immunosuppressive mode of action, we examined the therape utic effects of the malononitrilamides MNA 279 and MNA 715 in acute EA E, and two models of chronic relapsing EAE in Lewis rats and Biozzi mi ce. in the first model, sensitization of adult Lewis rats with guinea pig spinal cords resulted in an acute clinical episode of severe EAE, and by day 15 ail animals had died. Treatment of these sensitized rats with the MNAs was most effective in delaying and reducing the onset o f clinical symptoms, and mortality of acute EAE was prevented in a dos e-dependent manner The protection afforded by the two MNAs was long-la sting and no subsequent relapse was observed Similarly, in the chronic relapsing disease, aged Lewis rats were immunized with rabbit myelin basic protein, and ail untreated animals developed a disease with up t o three relapses. The second and third episodes were both milder and s horter in duration than the first. Aii animals treated with the MNAs s urvived the first attack, which also was delayed. Pathological signs w ere reduced and relapses did not occur: inhibition of chronic relapsin g EAE in aged Lewis rats was observed even when the MNA-treatment was started after the first appearance of clinical symptoms. Aii treated a nimals recovered completely and mortality was prevented. Also in the s econd model of chronic relapsing EAE in Biozzi AB/H mice, MNA treated animals showed only one acute and delayed episode and no further relap ses. Aii these results qualify both MNA 279 and MNA 715 as powerful im munosuppressants with therapeutic potential in human multiple sclerosi s (MS).