Therapeutic and adverse effects of a non-steroidal glucocorticoid receptor ligand in a mouse model of multiple sclerosis

• Published in: PloS one 2009-12, Vol.4 (12), p.e8202-e8202
• Main Authors: Wüst, Simone, Tischner, Denise, John, Michael, Tuckermann, Jan P, Menzfeld, Christiane, Hanisch, Uwe-Karsten, van den Brandt, Jens, Lühder, Fred, Reichardt, Holger M
• Format: Article
• Language: English
• Subjects: Acetates; Alkylation; Animal models; Animals; Apoptosis; Apoptosis - drug effects; Autoimmune diseases; Aziridines - pharmacology; Bcl-2 protein; Blood-brain barrier; Brain research; Caspase; CD44 antigen; Cell activation; Cell Adhesion Molecules - metabolism; Complications and side effects; Deoxyribonucleic acid; Diabetes and Endocrinology/Endocrinology; Disease Models, Animal; DNA; Dose-Response Relationship, Drug; Drug dosages; Embryo, Mammalian - cytology; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Experimental allergic encephalomyelitis; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene expression; Glucocorticoids; Guinea Pigs; Helper cells; Immunology; Immunology/Autoimmunity; Immunology/Immunomodulation; Inflammation; Inflammatory diseases; Interleukin 17; Interleukin-17 - biosynthesis; Intermediates; LFA-1 antigen; Ligands; Lymphocytes; Lymphocytes T; Magnetic resonance spectroscopy; Medical schools; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - pathology; Myelin; Myelin Sheath - drug effects; Myelin Sheath - metabolism; Nervous system; Neurological Disorders/Multiple Sclerosis and Related Disorders; Neuropathology; NMR; NMR spectroscopy; Nuclear magnetic resonance; Nuclear magnetic resonance spectroscopy; Organ Specificity - drug effects; Quaternary Ammonium Compounds - adverse effects; Quaternary Ammonium Compounds - pharmacology; Quaternary Ammonium Compounds - therapeutic use; Receptors, Glucocorticoid - metabolism; Repressing; Rodents; Side effects; Solvents; Spectroscopy; Steroids (Organic compounds); Synephrine - pharmacology; T cells; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Transcriptional Activation - drug effects; Tyramine - analogs & derivatives
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0008202

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). CpdA 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. (1)H 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. CpdA 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.