Antiinflammatory properties of a plant-derived nonsteroidal, dissociated glucocorticoid receptor modulator in experimental autoimmune encephalomyelitis.
Compound A (CpdA), a plant-derived phenyl aziridine precursor, was recently characterized as a fully dissociated nonsteroidal antiinflammatory agent, acting via activation of the glucocorticoid receptor, thereby down-modulating nuclear factor-kappaB-mediated transactivation, but not supporting glucocorticoid response element-driven gene expression. The present study demonstrates the effectiveness of CpdA in inhibiting the disease progress in experimental autoimmune encephalomyelitis (EAE), a well-characterized animal model of multiple sclerosis. CpdA treatment of mice, both early and at the peak of the disease, markedly suppressed the clinical symptoms of EAE induced by myelin oligodendrocyte glycoprotein peptide immunization. Attenuation of the clinical symptoms of EAE by CpdA was accompanied by reduced leukocyte infiltration in the spinal cord, reduced expression of inflammatory cytokines and chemokines, and reduced neuronal damage and demyelination. In vivo CpdA therapy suppressed the encephalogenicity of myelin oligodendrocyte glycoprotein peptide-specific T cells. Moreover, CpdA was able to inhibit TNF- and lipopolysaccharide-induced nuclear factor-kappaB activation in primary microglial cells in vitro, in a differential mechanistic manner as compared with dexamethasone. Finally, in EAE mice the therapeutic effect of CpdA, in contrast to that of dexamethasone, occurred in the absence of hyperinsulinemia and in the absence of a suppressive effect on the hypothalamic-pituitary-adrenal axis. Based on these results, we propose CpdA as a compound with promising antiinflammatory characteristics useful for therapeutic intervention in multiple sclerosis and other neuroinflammatory diseases.
van Loo
Geert
G
Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent University, B-9052 Ghent, Belgium. geert.vanloo@dmbr.vib-UGent.be
Sze
Mozes
M
Bougarne
Nadia
N
Praet
Jelle
J
Mc Guire
Conor
C
Ullrich
Andrea
A
Haegeman
Guy
G
Prinz
Marco
M
Beyaert
Rudi
R
De Bosscher
Karolien
K
D000085:Acetates; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003711:Demyelinating Diseases / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009103:Multiple Sclerosis / Q000188:drug therapy; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D021381:Protein Transport / Q000187:drug effects; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014439:Tyramine / Q000031:analogs & derivatives
C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D016328:NF-kappa B; D018696:Neuroprotective Agents; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014439:Tyramine