Abstract
Despite being a mainstay of inflammatory bowel disease (IBD) therapy, glucocorticoids (GCs) still carry significant risks with respect to unwanted side effects. Alternative drugs with a more favorable risk/benefit ratio than common GCs are thus highly desirable for the management of IBD. New and supposedly selective glucocorticoid receptor (GR) agonists (SEGRAs), with dissociated properties, have been described as promising candidates for circumventing therapeutic problems while still displaying full beneficial anti-inflammatory potency. Here, we report on compound A [CpdA; (2-((4-acetophenyl)-2-chloro-N-methyl)ethylammonium-chloride)] and N-(4-methyl-1-oxo-1H-2,3-benzoxazine-6-yl)-4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-2-(trifluoromethyl)-4-methylpentanamide (ZK216348), two GR agonists for the treatment of experimental colitis. Their therapeutic and anti-inflammatory effects were tested in the acute trinitrobenzene sulfonic acid-mediated colitis model in mice against dexamethasone (Dex). In addition to their influence on immunological pathways, a set of possible side effects, including impact on glucose homeostasis, steroid resistance, and induction of apoptosis, was surveyed. Our results showed that, comparable with Dex, treatment with CpdA and ZK216348 reduced the severity of wasting disease, macroscopic and microscopic damage, and colonic inflammation. However, both SEGRAs exhibited no GC-associated diabetogenic effects, hypothalamic pituitary adrenal axis suppression, or development of glucocorticoid resistance. In addition, CpdA and ZK216348 showed fewer transactivating properties and successfully dampened T helper 1 immune response. Unlike ZK216348, the therapeutic benefit of CpdA was lost at higher doses because of toxic apoptotic effects. In conclusion, both SEGRAs acted as potent anti-inflammatory agents with a significantly improved profile compared with classic GCs. Although CpdA revealed a narrow therapeutic window, both GR agonists might be seen as a starting point for a future IBD treatment option.
Footnotes
This work was supported by a graduate scholarship grant from the Deutsche Forschungsgemeinschaft [Grant GRK 757] (to K.C.R. and B.M.K.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- GC
- glucocorticoid
- GR
- GC receptor
- SEGRA
- selective GR agonist
- BW
- body weight
- COX
- cyclooxygenase
- CpdA
- compound A
- Dex
- dexamethasone
- ELISA
- enzyme-linked immunosorbent assay
- FACS
- fluorescence-activated cell sorting
- FCS
- fetal calf serum
- FL
- full length
- G-6-P
- glucose-6-phosphatase
- GRE
- glucocorticoid response element
- HEK
- human embryonic kidney
- HPA
- hypothalamic pituitary adrenal
- IBD
- inflammatory bowel disease
- IFN
- interferon
- IL
- interleukin
- LPS
- lipopolysaccharide
- Luc
- luciferase
- MCP-1
- monocyte chemotactic protein-1
- MLN
- mesenteric lymph node
- MPO
- myeloperoxidase
- MR
- mineralocorticoid receptor
- NF-κB
- nuclear factor-κB
- PARP
- poly(ADP-ribose) polymerase
- PBMC
- peripheral blood mononuclear cell
- PBS
- phosphate-buffered saline
- PEPCK
- phosphoenolpyruvate carboxykinase
- PCR
- polymerase chain reaction
- qPCR
- quantitative PCR
- PR
- progesterone receptor
- TAT
- tyrosine aminotransferase
- Th
- T helper
- TNBS
- trinitrobenzene sulfonic acid
- TNF
- tumor necrosis factor
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- ZK216348
- N-(4-methyl-1-oxo-1H-2,3-benzoxazine-6-yl)-4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-2-(trifluoromethyl)-4-methylpentanamide
- RU-486
- 11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.
- Received May 13, 2011.
- Accepted January 9, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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