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https://hdl.handle.net/2440/102853
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Type: | Journal article |
Title: | Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth |
Author: | Chin, P. Dorian, C. Hutchinson, M. Olson, D. Rice, K. Moldenhauer, L. Robertson, S. |
Citation: | Scientific Reports, 2016; 6(1):36112-1-36112-13 |
Publisher: | Nature Publishing Group |
Issue Date: | 2016 |
ISSN: | 2045-2322 2045-2322 |
Statement of Responsibility: | Peck Yin Chin, Camilla L. Dorian, Mark R. Hutchinson, David M. Olson, Kenner C. Rice, Lachlan M. Moldenhauer and Sarah A. Robertson |
Abstract: | Toll-like receptor 4 (TLR4) activation by bacterial infection, or by sterile inflammatory insult is a primary trigger of spontaneous preterm birth. Here we utilize mouse models to investigate the efficacy of a novel small molecule TLR4 antagonist, (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (-)-naloxone, in infection-associated preterm birth. Treatment with (+)-naloxone prevented preterm delivery and alleviated fetal demise in utero elicited by i.p. LPS administration in late gestation. A similar effect with protection from preterm birth and perinatal death, and partial correction of reduced birth weight and postnatal mortality, was conferred by (+)-naloxone administration after intrauterine administration of heat-killed E. coli. Local induction by E. coli of inflammatory cytokine genes Il1b, Il6, Tnf and Il10 in fetal membranes was suppressed by (+)-naloxone, and cytokine expression in the placenta, and uterine myometrium and decidua, was also attenuated. These data demonstrate that inhibition of TLR4 signaling with the novel TLR4 antagonist (+)-naloxone can suppress the inflammatory cascade of preterm parturition, to prevent preterm birth and perinatal death. Further studies are warranted to investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting. |
Keywords: | Animals Mice Premature Birth Inflammation Naloxone Lipopolysaccharides Cytokines Pregnancy Female Toll-Like Receptor 4 |
Description: | Published: 07 November 2016 |
Rights: | © The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
DOI: | 10.1038/srep36112 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1026178 http://purl.org/au-research/grants/nhmrc/465423 http://purl.org/au-research/grants/arc/DP110100297 |
Published version: | http://dx.doi.org/10.1038/srep36112 |
Appears in Collections: | Aurora harvest 7 IPAS publications |
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hdl_102853.pdf | Published version | 2.44 MB | Adobe PDF | View/Open |
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