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Antiinflammatory Properties of a Plant-Derived Nonsteroidal, Dissociated Glucocorticoid Receptor Modulator in Experimental Autoimmune Encephalomyelitis

Geert van Loo UGent, Mozes Sze UGent, Nadia Bougarne UGent, Jelle Praet, Conor Mc Guire UGent, Andrea Ullrich, Guy Haegeman UGent, Marco Prinz, Rudi Beyaert UGent and Karolien De Bosscher UGent (2010) MOLECULAR ENDOCRINOLOGY. 24(2). p.310-322
abstract
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- B-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- B 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
TRANSREPRESSION, ASTROCYTES, TRANSACTIVATION, NF-KAPPA-B, CENTRAL-NERVOUS-SYSTEM, AUTOREACTIVE T-CELLS, MULTIPLE-SCLEROSIS, INNATE IMMUNITY, IN-VIVO, GENE REPRESSION
journal title
MOLECULAR ENDOCRINOLOGY
Mol. Endocrinol.
volume
24
issue
2
pages
13 pages
publisher
ENDOCRINE SOC
place of publication
CHEVY CHASE
Web of Science type
Article
Web of Science id
000273976000004
JCR category
ENDOCRINOLOGY & METABOLISM
JCR impact factor
4.889 (2010)
JCR rank
21/115 (2010)
JCR quartile
1 (2010)
ISSN
0888-8809
DOI
10.1210/me.2009-0236
language
English
UGent publication?
yes
classification
A1
copyright statement
I don't know the status of the copyright for this publication
id
861789
handle
http://hdl.handle.net/1854/LU-861789
date created
2010-02-15 10:19:26
date last changed
2012-06-26 14:31:57
@article{861789,
  abstract     = {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- B-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- B 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.},
  author       = {van Loo, Geert and Sze, Mozes and Bougarne, Nadia and Praet, Jelle and Mc Guire, Conor and Ullrich, Andrea and Haegeman, Guy and Prinz, Marco and Beyaert, Rudi and De Bosscher, Karolien},
  issn         = {0888-8809},
  journal      = {MOLECULAR ENDOCRINOLOGY},
  keyword      = {TRANSREPRESSION,ASTROCYTES,TRANSACTIVATION,NF-KAPPA-B,CENTRAL-NERVOUS-SYSTEM,AUTOREACTIVE T-CELLS,MULTIPLE-SCLEROSIS,INNATE IMMUNITY,IN-VIVO,GENE REPRESSION},
  language     = {eng},
  number       = {2},
  pages        = {310--322},
  publisher    = {ENDOCRINE SOC},
  title        = {Antiinflammatory Properties of a Plant-Derived Nonsteroidal, Dissociated Glucocorticoid Receptor Modulator in Experimental Autoimmune Encephalomyelitis},
  url          = {http://dx.doi.org/10.1210/me.2009-0236},
  volume       = {24},
  year         = {2010},
}

Chicago
van Loo, Geert, Mozes Sze, Nadia Bougarne, Jelle Praet, Conor Mc Guire, Andrea Ullrich, Guy Haegeman, Marco Prinz, Rudi Beyaert, and Karolien De Bosscher. 2010. “Antiinflammatory Properties of a Plant-Derived Nonsteroidal, Dissociated Glucocorticoid Receptor Modulator in Experimental Autoimmune Encephalomyelitis.” Molecular Endocrinology 24 (2): 310–322.
APA
van Loo, Geert, Sze, M., Bougarne, N., Praet, J., Mc Guire, C., Ullrich, A., Haegeman, G., et al. (2010). Antiinflammatory Properties of a Plant-Derived Nonsteroidal, Dissociated Glucocorticoid Receptor Modulator in Experimental Autoimmune Encephalomyelitis. MOLECULAR ENDOCRINOLOGY, 24(2), 310–322.
Vancouver
1.
van Loo G, Sze M, Bougarne N, Praet J, Mc Guire C, Ullrich A, et al. Antiinflammatory Properties of a Plant-Derived Nonsteroidal, Dissociated Glucocorticoid Receptor Modulator in Experimental Autoimmune Encephalomyelitis. MOLECULAR ENDOCRINOLOGY. CHEVY CHASE: ENDOCRINE SOC; 2010;24(2):310–22.
MLA
van Loo, Geert, Mozes Sze, Nadia Bougarne, et al. “Antiinflammatory Properties of a Plant-Derived Nonsteroidal, Dissociated Glucocorticoid Receptor Modulator in Experimental Autoimmune Encephalomyelitis.” MOLECULAR ENDOCRINOLOGY 24.2 (2010): 310–322. Print.