Date Published: December 7, 2009
Publisher: Public Library of Science
Author(s): Simone Wüst, Denise Tischner, Michael John, Jan P. Tuckermann, Christiane Menzfeld, Uwe-Karsten Hanisch, Jens van den Brandt, Fred Lühder, Holger M. Reichardt, Jean Kanellopoulos. http://doi.org/10.1371/journal.pone.0008202
Abstract: Dissociating glucocorticoid receptor (GR) ligands hold great promise for treating inflammatory disorders since it is assumed that they exert beneficial activities mediated by transrepression but avoid adverse effects of GR action requiring transactivation. Here we challenged this paradigm by investigating 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride (CpdA), a dissociating non-steroidal GR ligand, in the context of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).
Partial Text: Glucocorticoids (GCs) are amongst the most potent anti-inflammatory drugs presently available and are widely used to treat chronic inflammatory diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) –. Nevertheless, GC therapy is often complicated by severe adverse effects such as osteoporosis, muscle atrophy or diabetes , . Therefore, it remains a challenge to develop new GC analogues with similar efficacy but reduced side effects.
GCs are highly potent anti-inflammatory drugs that are used to treat a variety of diseases such as RA, asthma or MS , , . Nevertheless, systemic application is often accompanied by unfavorable adverse effects complicating long term GC therapy . Since it is believed that beneficial effects are often mediated by GR transrepression while many side effects rely on GR transactivation, current research aims at identifying novel substances that dissociate these two features. A promising candidate for such a drug is CpdA . In this work we could show that CpdA indeed represses inflammatory mediators in myelin-specific T effector cells and fibroblasts in vitro in the absence of gene activation. However, we found that CpdA added at the same concentration also induces apoptosis in various cell-types such as lymphocytes and neuronal cells. This activity of CpdA proceeds via a Bcl-2- and caspase-dependent pathway and is fully independent of the GR. A likely explanation for the dichotomy observed in cell culture comes from our 1H NMR results. Despite acting in principle as a dissociating GR-ligand, CpdA dissolved in buffered solutions rapidly decomposes into aziridine derivatives that are generally known as alkylating agents with strong pro-apoptotic and neurotoxic potential , .