Abstract
Prostaglandin E2 receptor subtype 4 (EP4) agonists are known to reduce intestinal inflammation and enhance epithelium regeneration. We explored the possibility of colonic delivery of an EP4 agonist, 2-[(4-{[2-((1R,2R,3R)-3-hydroxy-2-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoyl)oxy]ethyl nonanoate (ONO-AE2-724), using poly(lactic-coglycolic acid) (PLGA) microspheres. Colitis was induced in mice by the intrarectal administration of trinitrobenzene sulfonic acid (TNBS). ONO-AE2-724-PLGA microspheres (EP4-MS) were prepared by the standard technique. Drug distributions after oral administration of EP4-MS were determined by liquid chromatography-tandem mass spectrometry analysis. To evaluate the protective effect of EP4-MS, animals were orally treated by gavage with single doses of EP4-MS 24 h before TNBS instillation. The changes in body weight, histopathology, immunohistochemistry, and expression of inflammatory cytokines were evaluated. Oral administration of EP4-MS enhanced colonic tissue drug concentration without any increase in the serum concentration during the 48 h after intake. EP4-MS pretreatment, but not unloaded ONO-AE2-724, significantly attenuated TNBS-induced colitis and diminished colonic mRNA expression levels of proinflammatory cytokines. In addition, a significant increase in the expression of CD25 and FoxP3 was found in isolated lamina propria CD4+ T cells of EP4-MS-treated mice. Immunohistochemical analysis of Ki-67 and single-stranded DNA revealed that EP4-MS pretreatment significantly suppressed apoptosis of colonic cells and promoted epithelial cell proliferation. These results suggest that EP4-MS protect mice from TNBS-induced colitis by intestinal local ONO-AE2-724 delivery. The EP4-MS may offer a promising new therapeutic strategy to treat inflammatory bowel diseases.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- IBD
- inflammatory bowel disease
- UC
- ulcerative colitis
- PG
- prostaglandin
- EP4
- PGE2 receptor subtype 4
- 5-ASA
- 5-aminnosalicylic acid
- PLGA
- poly(lactic-coglycolic acid)
- ONO-AE2-724
- 2-[(4-{[2-((1R,2R,3R)-3-hydroxy-2-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl) phenyl]but-1-enyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoyl)oxy]ethyl nonanoate
- EP4-MS
- ONO-AE2-724-loaded PLGA microspheres
- TNBS
- trinitrobenzene sulfonic acid
- ONO-AE1-437
- de-esterificated active form of ONO-AE2-724
- HPLC
- high-performance liquid chromatography
- MS
- unloaded PLGA microspheres
- PBS
- phosphate-buffered saline
- LC
- liquid chromatography
- MS/MS
- mass spectrometry
- ONO-AE2-247
- deuterium labeled form of ONO-AE1-437
- ONO-4819CD
- [[3-[[(1R)-2β-[(3S)-3-Hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl]-3α-hydroxy-5-oxocyclopentane-1α-yl]thio]propyl]thio]acetic acid chloridin
- H&E
- hematoxylin and eosin
- PAS
- periodic acid-Schiff
- ssDNA
- single-strand DNA
- PCR
- polymerase chain reaction
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- ELISA
- enzyme-linked immunosorbent assay
- IL
- interleukin
- LPL
- lamina propria lymphocyte
- Foxp3
- transcription factor forkhead box P3
- TNF-α
- tumor necrosis factor-α
- IFN-γ
- interferon-γ
- TGF-β1
- transforming growth factor-β1
- Treg
- regulatory T cell.
- Received November 28, 2011.
- Accepted February 1, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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