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Scientific ReportsPharmacology & ToxicologyPeer-reviewed journal article

N,N-dimethylacetamide blocks inflammation-induced preterm birth and remediates maternal systemic immune responses

Sandra E. ReznikiD, Alexander KashouiD, Daylan Ward, Steven M. YelloniD

PDFDOIPreprint

In-depth summary

Claude Sonnet 4.6 · xhigh effort · 8 Nov 2026 · from the full text of version 1 (20 Jan 2025) · CC BY 4.0

A two-dose DMA regimen on gestational day 15 prevented LPS-induced preterm birth in CD-1 mice, reversed cytokine surges within days, and spared term parturition.

Preterm birth remains a leading cause of neonatal morbidity and mortality, and the drug pipeline has no candidates able to block premature delivery. This work tests whether DMA, an NF-κB-inhibiting drug excipient, can curb LPS-driven maternal systemic inflammation and premature cervical remodeling and carry pregnancy to term.

Key results

  1. ShownLPS caused preterm delivery in most treated dams, while co-treatment with DMA let pregnancies continue to roughly term on a timeline similar to saline and DMA-only controls.

    9 of 13 LPS mice (69.2%) delivered preterm, with birth within 24 h by day 16 postbreeding; DMA+LPS dams delivered on average at term. Kaplan-Meier group sizes were n=20 Con, 18 LPS, 15 DMA, 23 DMA+LPS. · DMA prevents LPS-induced preterm birth and…; Figure legends

  2. ShownLPS raised all ten measured cytokines in maternal plasma regardless of DMA. DMA then reversed the trajectory, and by day 18 levels matched controls for all but GM-CSF, which rebounded after day 18. Only G-CSF and TNFα differed significantly from LPS alone at day 16.

    LPS gave a greater than 10-fold rise in all ten cytokines within 12 h; in DMA+LPS the direction reversed between D15.5 and D16; significant LPS vs DMA+LPS difference at D16 for G-CSF and TNFα only; n=3-9/group/day. · DMA remediates LPS-induced responses by…; Discussion; Figure legends

  3. ShownDMA did not prevent the early LPS-induced progesterone drop, but progesterone recovered and stayed elevated in DMA+LPS dams, whereas it fell to baseline in dams delivering preterm after LPS. This is consistent with a progesterone-independent rescue.

    Progesterone was suppressed at D15.5 in both LPS and DMA+LPS vs their controls; by D16 it was at baseline in 9 postpartum LPS mice but elevated in DMA+LPS through D18; n=3-8/group/time. · DMA prevents LPS-induced preterm birth and…; Discussion; Figure legends

  4. SuggestedDMA delayed LPS-triggered cervical changes (nuclei density loss, a proxy for edema) and blunted prepartum loss of cross-linked collagen, without blocking parturition at term.

    Cervical nuclei density was unchanged at D16 in DMA+LPS but fell by D16 in LPS mice; it dropped by D18 in DMA+LPS like controls. DMA blunted the prepartum OD/CN rise (p>0.05). n=3-7 mice/day. · DMA remediates LPS-induced responses by…; Discussion; Figure legends

  5. ShownThe DMA+LPS group had notable pup morbidity and some dam deaths, higher than saline controls and DMA-only dams.

    Pup morbidity or mortality: Con 0.7% (2 of 269), DMA 12% (23 of 187), DMA+LPS 30% (104 of 344). Two of 28 DMA+LPS dams (7%) died within 2 days of treatment; no maternal deaths in Con, DMA or LPS. · DMA prevents LPS-induced preterm birth and…

Methods, data and reproducibility

Timed-pregnant CD-1 mice received intraperitoneal saline, DMA, LPS, or DMA+LPS on gestational day 15. Birth timing was recorded; plasma progesterone (ELISA) and ten cytokines (multiplex) were measured, and cervix collagen cross-linking and nuclei density were quantified histologically.

  • Nulliparous timed-pregnant CD-1 mice in four groups (saline, DMA, LPS, DMA+LPS); birth-timing Kaplan-Meier cohort · mouse · n = 20 Con, 18 LPS, 15 DMA, 23 DMA+LPS
  • Plasma progesterone and ten-cytokine measurements at D15.5, D16, D18 and postpartum · mouse · n = 3-8/group/time (progesterone); 3-9/group/day (cytokines)
  • Cervix stroma sections (ectocervix and endocervix): picrosirius red optical density and methyl green nuclei counts · mouse · n = 3-7 mice/day
  • Pilot LPS dose-range study (50-100 µg per 0.1 ml) to select a dose giving preterm birth · mouse · n = 3/group
Methods & tools
N,N-dimethylacetamide (DMA) i.p. treatment, LPS serotype O55:B5, Enzo mouse progesterone ELISA (ADI-900-011), Bio-Plex 200 with custom multiplex kits, Picrosirius red polarized-light birefringence, Methyl green nuclei staining, Visiopharm automated nuclei-counting algorithm, Grubbs and Levene tests, 1-way and 2-way ANOVA with Tukey/Sidak, Kruskal-Wallis with Dunn test
Reproducibility gaps
Data are said to be in the paper and its Supplement only; no repository accession is given. The Visiopharm nuclei-counting algorithm is validated in the Supplement but no code link appears.
Limitations (5)
  • The endotoxin model captures only one common route to early delivery and does not cover every cause of birth before 37 weeks; it may also understate silent systemic or local inflammation. · stated by the authors
  • Pups were allowed to nurse for only 4 h, and DMA reproductive toxicity, pharmacokinetics and route of administration were not studied; these are deferred to future work. · stated by the authors
  • The authors note that concerns about DMA teratogenicity persist and that animal models have known limitations, so any use of circulating markers to forecast preterm risk in more advanced mammals remains conceivable but untested. · stated by the authors
  • Mechanistic claims (NF-κB, prostaglandin F2α, progesterone sensitivity) are inferred rather than tested. Per-time-point sample sizes are small (3-9), and only G-CSF and TNFα differed significantly between LPS and DMA+LPS at D16. · noted in this summary
  • Only one DMA schedule was tested, with LPS at 70 or 80 µg, and there was no DMA dose-response. The higher pup morbidity (30%) and dam deaths in DMA+LPS leave the safety margin unclear. · noted in this summary

Read this if you study inflammation-driven preterm birth models, maternal cytokine time courses, or anti-inflammatory tocolytic candidates tested in mice.

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Abstract

The common excipient, N,N-dimethylacetamide (DMA), prevents imminent endotoxin-induced preterm birth in mice. The present study hypothesized that DMA forestalls preterm birth to term (defined as day 18.5 or later) by attenuating bacterial endotoxin lipopolysaccharide (LPS)-induced maternal systemic inflammatory responses and cervix remodeling. Accordingly, LPS (i.p.) on day 15 postbreeding stimulated preterm delivery within 24 h while mice treated with DMA 2 h preceding and 9 h following LPS administration remained pregnant, comparable to saline and DMA controls, to deliver viable pups at term. Irrespective of LPS or DMA+LPS treatment, maternal plasma pro- and anti-inflammatory cytokines on day 15.5 (12 h post-LPS) increased 10-fold compared to baseline concentrations in controls. On day 16 of pregnancy, plasma concentrations of G-CSF and TNF were reduced in the prepartum LPS+DMA group compared to those in postpartum mice given LPS. By day 18 of pregnancy, all cytokines returned to baseline - equivalent to low systemic levels throughout the study in saline and DMA controls that gave birth at term. In addition, maternal plasma progesterone declined within 12 h in prepartum LPS-treated mice to postpartum concentrations on day 16. Although a similar transient decrease occurred by 12 h in DMA+LPS mice, plasma progesterone returned to baseline concentrations in controls. Contemporaneously, the progression of prepartum cervix remodeling leading to preterm delivery was acutely forestalled by DMA without impeding birth at term. These findings support the hypothesis that DMA not only prevents inflammation-driven preterm birth, but rescues pregnancy for birth to occur at term. The results raise the possibility that maternal signals can forecast risk of preterm birth while selective suppression of systemic inflammation can mitigate adverse pregnancy outcomes. SummaryDMA rescues pregnancy from inflammation-induced preterm birth through a progesterone-independent mechanism that involves multiple proinflammatory cytokines in maternal circulation. Supported by NIH Grant 1R16GM145586 and the Ines Mandl Research Foundation

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