SRI 62-834, a cyclic ether analogue of the phospholipid ET-18-OCH3, displays long-lasting beneficial effect in chronic relapsing experimental allergic encephalomyelitis in the Lewis rat. Comparison with cyclosporin and (Val2)-dihydrocyclosporin effects in clinical, functional and histological studies.
The therapeutic effect of the ether phospholipid SRI 62-834, which lacks the characteristics of an immunosuppressive agent, was compared with those of two immunosuppressive drugs, cyclosporin and valine2-dihydrocyclosporin, in a rat model of chronic relapsing experimental allergic encephalomyelitis (CR-EAE). Drug treatment was initiated at the beginning of the first spontaneous remission on day 15 and was discontinued on day 31. Whereas the untreated rats experienced two paralytic relapses around days 21 and 31, the progression of CR-EAE was prevented during the period of drug administration. Protection with both cyclosporin and its derivative was complete, but SRI 62-834 only attenuated the clinical disease. The absence of paralytic symptoms was reflected by a distinct reduction in mononuclear cell infiltration in the central nervous system at days 21 and 31 in treated animals. The main difference between the two drug classes became apparent after withdrawal of therapy. Discontinuation of SRI 62-834 resulted in a long-lasting beneficial effect, with the rats remaining clinically normal and showing no histopathological changes. However, cyclosporin only delayed the clinical symptoms which reappeared after cessation of treatment. The exacerbated paralytic relapse, which followed about 1 week later and was associated with severe perivascular cell infiltrates and tissue destruction, subsequently became chronic in several animals. By contrast, withdrawal of valine2-dihydrocyclosporin partially prevented disease relapse and markedly reduced severity of symptoms without progression of a chronic disease. These results demonstrate the clear differences in the mode of action of these compounds in CR-EAE and suggest that SRI 62-834 could be an interesting candidate for the treatment of multiple sclerosis.
Chabannes
D
D
Preclinical Research, Sandoz Pharma Ltd, Basel, Switzerland.
Ryffel
B
B
Borel
J F
JF
D000818:Animals; D002465:Cell Movement; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use*; D003524:Cyclosporins / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D009103:Multiple Sclerosis; D010742:Phospholipid Ethers / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D012008:Recurrence; D012074:Remission Induction
D003524:Cyclosporins; D005663:Furans; D007166:Immunosuppressive Agents; D010742:Phospholipid Ethers; C055462:SRI 62-834; C041326:dihydrocyclosporin D; D016572:Cyclosporine