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A Novel Topical PPAR 3 Agonist Induces PPAR 3 Activity in Ulcerative Colitis Mucosa and Prevents and Reverses Inflammation in Induced Colitis Models

Da Silva, Stéphanie ; Keita, Åsa V. ; Mohlin, Sofie LU orcid ; Påhlman, Sven LU ; Theodorou, Vassilia ; Påhlman, Ingrid ; Mattson, Jan P. and Söderholm, Johan D. (2018) In Inflammatory Bowel Diseases 24(4). p.792-805
Abstract

Background Peroxisome proliferator-activated receptor-gamma (PPAR 3) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPAR 3 agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis. Methods Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPAR 3-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay). AS002 absorption was determined in the colonic mucosa of... (More)

Background Peroxisome proliferator-activated receptor-gamma (PPAR 3) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPAR 3 agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis. Methods Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPAR 3-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay). AS002 absorption was determined in the colonic mucosa of UC patients. DSS-colitis mice received PPAR 3 agonists or vehicle daily by intrarectal administration starting 2 days before induction of colitis (preventive) or from days 3 to 8 (curative). Myeloperoxidase (MPO) and cytokine levels in colonic mucosa were determined. In addition, AS002 effects were studied in TNBS colitis. Results AS002 displayed an absorption pattern of a lipophilic drug totally metabolized in the mucosa. AS002 and rosiglitazone increased ADIPOPHILIN mRNA expression (3-fold) and decreased TNF-α, IL-1β, and IL-13 levels in human UC biopsies. In DSS, in both preventive and curative treatment and in TNBS colitis, AS002 protected against macroscopic and histological damage and lowered MPO and TNF-α, IL-1β, and IL-13 levels. Conclusions AS002 triggers anti-inflammatory PPAR 3 activity in the human colonic mucosa of UC patients and prevents and reverses colitis in mice. Our data suggest that AS002 has potential for topical maintenance treatment of UC, which warrants further studies in vivo in patients.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
animal model, inflammatory bowel disease, PPAR gamma, ulcerative colitis
in
Inflammatory Bowel Diseases
volume
24
issue
4
pages
14 pages
publisher
Oxford University Press
external identifiers
  • scopus:85044481100
  • pmid:29529198
ISSN
1078-0998
DOI
10.1093/ibd/izx079
language
English
LU publication?
yes
id
e206478c-0aa0-4d1a-9654-ec1b1d1f16ff
date added to LUP
2018-05-07 13:46:18
date last changed
2024-04-15 06:31:06
@article{e206478c-0aa0-4d1a-9654-ec1b1d1f16ff,
  abstract     = {{<p>Background Peroxisome proliferator-activated receptor-gamma (PPAR 3) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPAR 3 agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis. Methods Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPAR 3-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay). AS002 absorption was determined in the colonic mucosa of UC patients. DSS-colitis mice received PPAR 3 agonists or vehicle daily by intrarectal administration starting 2 days before induction of colitis (preventive) or from days 3 to 8 (curative). Myeloperoxidase (MPO) and cytokine levels in colonic mucosa were determined. In addition, AS002 effects were studied in TNBS colitis. Results AS002 displayed an absorption pattern of a lipophilic drug totally metabolized in the mucosa. AS002 and rosiglitazone increased ADIPOPHILIN mRNA expression (3-fold) and decreased TNF-α, IL-1β, and IL-13 levels in human UC biopsies. In DSS, in both preventive and curative treatment and in TNBS colitis, AS002 protected against macroscopic and histological damage and lowered MPO and TNF-α, IL-1β, and IL-13 levels. Conclusions AS002 triggers anti-inflammatory PPAR 3 activity in the human colonic mucosa of UC patients and prevents and reverses colitis in mice. Our data suggest that AS002 has potential for topical maintenance treatment of UC, which warrants further studies in vivo in patients.</p>}},
  author       = {{Da Silva, Stéphanie and Keita, Åsa V. and Mohlin, Sofie and Påhlman, Sven and Theodorou, Vassilia and Påhlman, Ingrid and Mattson, Jan P. and Söderholm, Johan D.}},
  issn         = {{1078-0998}},
  keywords     = {{animal model; inflammatory bowel disease; PPAR gamma; ulcerative colitis}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{4}},
  pages        = {{792--805}},
  publisher    = {{Oxford University Press}},
  series       = {{Inflammatory Bowel Diseases}},
  title        = {{A Novel Topical PPAR 3 Agonist Induces PPAR 3 Activity in Ulcerative Colitis Mucosa and Prevents and Reverses Inflammation in Induced Colitis Models}},
  url          = {{http://dx.doi.org/10.1093/ibd/izx079}},
  doi          = {{10.1093/ibd/izx079}},
  volume       = {{24}},
  year         = {{2018}},
}