Abstract
BackgroundDissociating 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).Methodology/Principal FindingsCpdA inhibited pro-inflammatory mediators in myelin-specific T cells and fibroblasts in a GR-dependent manner while gene activation was abolished. However, it also induced massive apoptosis in various cell types even in the absence of the GR by engaging a Bcl-2- and caspase-dependent pathway. 1H NMR spectroscopy corroborated these findings by revealing that CpdA dissolved in buffered solutions rapidly decomposes into aziridine intermediates known to act as alkylating pro-apoptotic agents. Importantly, the dichotomy of CpdA action also became evident in vivo. Administration of high-dose CpdA to mice was lethal while treatment of EAE with low to intermediate amounts of CpdA dissolved in water significantly ameliorated the disease. The beneficial effect of CpdA required expression of the GR in T cells and was achieved by down regulating LFA-1 and CD44 on peripheral Th cells and by repressing IL-17 production.Conclusions/SignificanceCpdA has significant therapeutic potential although adverse effects severely compromise its application in vivo. Hence, non-steroidal GR ligands require careful analysis prior to their translation into new therapeutic concepts.
Highlights
Glucocorticoids (GCs) are amongst the most potent antiinflammatory drugs presently available and are widely used to treat chronic inflammatory diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) [1,2,3]
Addition of 1025 M CpdA did not alter the expression of the bona fide glucocorticoid receptor (GR) target gene glucocorticoid-induced leucin zipper (GILZ) in Tenc cells while treatment with 1026 M Dex strongly increased it (Fig. 1B)
No apoptosis was detected within the 5 hrs culture period, excluding that the observed effects were linked to cell death
Summary
Glucocorticoids (GCs) are amongst the most potent antiinflammatory drugs presently available and are widely used to treat chronic inflammatory diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) [1,2,3]. Several cytokines in these mice are fully repressed by GC treatment while regulation of many genes involved in metabolic side effects is abolished [8,9] This model stimulated the search for new dissociating GR ligands that predominantly act via transrepression such as ZK 216348 [10], AL-438 [11] or 2-(4-. 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. We challenged this paradigm by investigating 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride (CpdA), a dissociating non-steroidal GR ligand, in the context of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS)
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