Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth.
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.
Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Peck Yin
PY
Chin
Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Camilla L
CL
Dorian
Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.|Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA, 5005, Australia.
Mark R
MR
Hutchinson
Departments of Obstetrics &Gynecology, Pediatrics and Physiology, University of Alberta, Edmonton, Alberta T6G2S2, Canada.
David M
DM
Olson
Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20892, USA.
Kenner C
KC
Rice
Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Lachlan M
LM
Moldenhauer
Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Sarah A
SA
Robertson
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D009270:Naloxone / Q000494:pharmacology*; D011247:Pregnancy; D047928:Premature Birth / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009270:Naloxone