Prevention and treatment of experimental autoimmune encephalomyelitis by CNI-1493, a macrophage-deactivating agent.
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are characterized by episodic neurologic dysfunction, perivascular mononuclear cell inflammation occurring mainly in white matter, and demyelination. Strong circumstantial evidence supports the conclusion that macrophage activation and local production of proinflammatory cytokines are necessary for disease induction and lesion formation. We now report that CNI-1493, a small m.w. compound, which inhibits macrophage activation and subsequent proinflammatory cytokine production, suppresses EAE induced in the genetically susceptible SJL/J mouse. Treatment with 5 mg/kg/day completely suppressed mild disease (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 acute disease (clinical index of 4.3 +/- 0.7 in the untreated group as compared with 0.5 +/- 0.3 for the treated group). Suppression of clinical manifestations of the disease correlated with a significant decrease in histopathology and proinflammatory cytokine expression at the lesion site. Moreover, drug treatment during the chronic phase resulted in amelioration of clinical signs. The data presented here should prove useful in developing novel chemotherapeutic approaches for the treatment of MS.
Martiney
J A
JA
The Picower Institute for Medical Research, Manhasset, NY 11030, USA. martiney@kswl.org
Rajan
A J
AJ
Charles
P C
PC
Cerami
A
A
Ulrich
P C
PC
Macphail
S
S
Tracey
K J
KJ
Brosnan
C F
CF
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002908:Chronic Disease; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006835:Hydrazones / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D012008:Recurrence; D013116:Spinal Cord / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D000813:Anilides; D006146:Guanidines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D006835:Hydrazones; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; C097256:semapimod; D000813:Anilides; D006146:Guanidines