One of the most established roles of oxytocin (OT) is in inducing uterine contractions and labour. Apart from contractions, our recent study have shown that OT can also activate pro-inflammatory pathways in both human myometrial and amnion cells which suggests the pro-inflammatory role of OT should be taken into account when developing tocolytics targeting the OT/OT receptor (OT/OTR) system. The OTR antagonist, Atosiban, is currently used therapeutically for the treatment of PTL. We have previously shown that Atosiban fails to inhibit the pro-inflammatory effects of OT in human amnion, and Atosiban alone activates NF-κB and MAPKs thus upregulating downstream pro-labour genes. In contrast to our findings with Atosiban, the presence of the orally active OTR antagonist, Nolasiban, reduced the effect of OT on NF-κB and p38 kinase activation both in myometrial and amnion cells. Consistent with the activation of these inflammatory mediators, OT led to increases in the expression of COX-2 and p-cPLA2, which was reflected in PGE2 synthesis. Inhibition of NF-κB activation by Nolasiban also translated to suppression of downstream pro-labour gene expression such as COX-2, CCL2, IL-6, and IL-8. We have also demonstrated that Nolasiban treatment alone has no significant stimulatory effect on both the myometrium and amnion. In conclusion, our findings indicate that Nolasiban possesses a promising potential as a novel tocolytic agent for both acute and maintenance therapy as it inhibits both myometrial contractions and the pro-inflammatory effects of OT without the biased agonist effects.
- The American Society for Pharmacology and Experimental Therapeutics