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Novel Selective Estrogen Receptor Modulator Ameliorates Murine Colitis.

Authors
  • Polari, Lauri1, 2
  • Anttila, Santeri3
  • Helenius, Terhi4
  • Wiklund, Anu5
  • Linnanen, Tero6
  • Toivola, Diana M7, 8
  • Määttä, Jorma9, 10
  • 1 Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland. [email protected] , (Finland)
  • 2 Faculty of Science and Engineering, Department Biosciences, Cell Biology; Åbo Akademi University, FI-20520 Turku, Finland. [email protected] , (Finland)
  • 3 Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland. [email protected] , (Finland)
  • 4 Faculty of Science and Engineering, Department Biosciences, Cell Biology; Åbo Akademi University, FI-20520 Turku, Finland. [email protected] , (Finland)
  • 5 Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland. [email protected] , (Finland)
  • 6 Forendo Pharma Ltd., FI-20520 Turku, Finland. [email protected] , (Finland)
  • 7 Faculty of Science and Engineering, Department Biosciences, Cell Biology; Åbo Akademi University, FI-20520 Turku, Finland. [email protected] , (Finland)
  • 8 Turku Center for Disease Modeling, FI-20520 Turku, Finland. [email protected] , (Finland)
  • 9 Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland. [email protected] , (Finland)
  • 10 Turku Center for Disease Modeling, FI-20520 Turku, Finland. [email protected] , (Finland)
Type
Published Article
Journal
International Journal of Molecular Sciences
Publisher
MDPI AG
Publication Date
Jun 20, 2019
Volume
20
Issue
12
Identifiers
DOI: 10.3390/ijms20123007
PMID: 31226730
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Estrogen-receptor-mediated signaling has been suggested to decrease the inflammatory response in monocyte macrophages. Previously, we showed that a novel selective estrogen receptor modulator (SERM2) promotes anti-inflammatory phenotype of monocytes in vitro. In this study, we demonstrate the potential of SERM2 in amelioration of colitis. We utilized a dextran sodium sulfate (DSS)-induced colitis model in FVB/n mice to demonstrate the effects of orally administered SERM2 on the clinical status of the mice and the histopathological changes in the colon, as well as proportion of Mrc-1 positive macrophages. SERM2 nuclear receptor affinities were measured by radioligand binding assays. Orally administered, this compound significantly alleviated DSS-induced colitis in male mice and induced local estrogen receptor activation in the inflamed colon, as well as promoting anti-inflammatory cytokine expression and infiltration of anti-inflammatory monocytes. We show that this novel drug candidate has an affinity to estrogen receptors α and β and progesterone receptors, but not to glucocorticoid receptor, thus expressing unique binding properties compared to other sex steroid receptor ligands. These results indicate that novel drug candidates to alleviate inflammatory conditions of the colon could be found among sex steroid receptor activating compounds.

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