The inhibitory effect in experimental autoimmune encephalomyelitis by the immunomodulatory drug Linomide (PNU-212616) is not mediated via release of endogenous glucocorticoids.
The immunomodulatory drug Linomide (PNU-212616) is an efficient inhibitor of experimental autoimmune encephalomyelitis (EAE) and a variety of other models of autoimmunity. The mechanism of action of the drug is, however, incompletely resolved. It was recently suggested that Linomide might exert its immunomodulatory activity by stimulation of the hypothalamic-pituitary-adrenal axis. To investigate the relevance of this mechanism of action, we monitored the plasma levels of endogenous corticosterone after treatment with Linomide, and also directly compared the inhibitory activity of the drug on acute EAE induced in sham or adrenalectomized SJL/N mice. Treatment with Linomide resulted in a dose related inhibition of EAE in line with previously reported results. Upon onset of clinical signs of EAE, there was a 7-10 fold elevation of plasma corticosterone from the normal baseline level. Administration of Linomide did however not by itself result in any change in plasma corticosterone levels, neither at the pre-symptomatic phase of the disease nor during acute short term treatment. In adrenal ectomized animals immunized for EAE, paralytic disease developed rapidly and was of a more severe and fatal nature as compared to sham-operated controls. Treatment with Linomide had a profound inhibitory effect on development of paralytic disease in both the ectomized and sham-operated groups. These results strongly suggest that Linomide does not exert its immunomodulatory activity via the release of endogenous glucocorticoids.
Pekarski
O
O
Department of Experimental Therapy, Lund Research Center, Pharmacia and Upjohn, Sweden. olga.pekarski@eu.pnu.com
Björk
J
J
Hedlund
G
G
Andersson
G
G
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000315:Adrenalectomy; D000818:Animals; D003345:Corticosterone / Q000097:blood / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D005260:Female; D005938:Glucocorticoids / Q000097:blood / Q000276:immunology*; D006912:Hydroxyquinolines / Q000276:immunology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL
D000276:Adjuvants, Immunologic; D005938:Glucocorticoids; D006912:Hydroxyquinolines; C045282:roquinimex; D003345:Corticosterone