INT-767-A Dual Farnesoid-X Receptor (FXR) and Takeda G Protein-Coupled Receptor-5 (TGR5) Agonist Improves Survival in Rats and Attenuates Intestinal Ischemia Reperfusion Injury.
Farnesoid-X receptor (FXR)
Takeda G protein-coupled Receptor 5 (TGR5)
intestinal ischemia reperfusion injury
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
04 Oct 2023
04 Oct 2023
Historique:
received:
25
03
2023
revised:
25
09
2023
accepted:
30
09
2023
medline:
1
11
2023
pubmed:
14
10
2023
entrez:
14
10
2023
Statut:
epublish
Résumé
Intestinal ischemia is a potentially catastrophic emergency, with a high rate of morbidity and mortality. Currently, no specific pharmacological treatments are available. Previous work demonstrated that pre-treatment with obeticholic acid (OCA) protected against ischemia reperfusion injury (IRI). Recently, a more potent and water-soluble version has been synthesized: Intercept 767 (INT-767). The aim of this study was to investigate if intravenous treatment with INT-767 can improve outcomes after IRI. In a validated rat model of IRI (60 min ischemia + 60 min reperfusion), three groups were investigated (n = 6/group): (i) sham: surgery without ischemia; (ii) IRI + vehicle; and (iii) IRI + INT-767. The vehicle (0.9% NaCl) or INT-767 (10 mg/kg) were administered intravenously 15 min after start of ischemia. Endpoints were 7-day survival, serum injury markers (L-lactate and I-FABP), histology (Park-Chiu and villus length), permeability (transepithelial electrical resistance and endotoxin translocation), and cytokine expression. Untreated, IRI was uniformly lethal by provoking severe inflammation and structural damage, leading to translocation and sepsis. INT-767 treatment significantly improved survival by reducing inflammation and preserving intestinal structural integrity. This study demonstrates that treatment with INT-767 15 min after onset of intestinal ischemia significantly decreases IRI and improves survival. The ability to administer INT-767 intravenously greatly enhances its clinical potential.
Identifiants
pubmed: 37834329
pii: ijms241914881
doi: 10.3390/ijms241914881
pmc: PMC10573246
pii:
doi:
Substances chimiques
6-ethyl-24-norcholane-3,7,23-triol-23 sulfate
0
Receptors, G-Protein-Coupled
0
farnesoid X-activated receptor
0C5V0MRU6P
Receptors, Cytoplasmic and Nuclear
0
Bile Acids and Salts
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Society for Organ Transplantation
ID : EC is supported by an unrestricted ESOT (European Society of Transplantation) Transplant Fel-lowship Grant
Organisme : Research Foundation - Flanders
ID : TV is supported by the Flanders Research Foundation (FWO Vlaanderen) through a senior clini-cal research mandate (1830517N)
Organisme : KU Leuven
ID : JP is supported by a chair at KU Leuven, funded by Institut George Lopez (IGL)
Organisme : KU Leuven
ID : LJC is supported by a chair at KU Leuven, funded by Medtronic
Organisme : University Hospitals Leuven
ID : LJC is supported by a post-doc research fellowship funded by University Hospitals Leuven (KOOR-UZ Leuven)
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