N,N-Dimethylformamide Delays LPS-Induced Preterm Birth in a Murine Model by Suppressing the Inflammatory Response

Zeng Hui Wei, Oluwabukola O. Salami, Jagadish Koya, Swapna Munnangi, Ryan Pekson, Charles R. Ashby, Sandra E. Reznik

Research output: Contribution to journalArticlepeer-review

Abstract

Preterm birth accounts for the majority of perinatal mortality worldwide, and there remains no FDA-approved drug to prevent it. Recently, we discovered that the common drug excipient, N,N-dimethylacetamide (DMA), delays inflammation-induced preterm birth in mice by inhibiting NF-κB. Since we reported this finding, it has come to light that a group of widely used, structurally related aprotic solvents, including DMA, N-methyl-2-pyrrolidone (NMP) and dimethylformamide (DMF), have anti-inflammatory efficacy. We show here that DMF suppresses LPS-induced TNFα secretion from RAW 264.7 cells and IL-6 and IL-8 secretion from HTR-8 cells at concentrations that do not significantly affect cell viability. Like DMA, DMF protects IκBα from degradation and prevents the p65 subunit of NF-κB from translocating to the nucleus. In vivo, DMF decreases LPS-induced inflammatory cell infiltration and expression of TNFα and IL-6 in the placental labyrinth, all to near baseline levels. Finally, DMF decreases the rate of preterm birth in LPS-induced pregnant mice (P<.0001) and the rate at which pups are spontaneously aborted (P<.0001). In summary, DMF, a widely used solvent structurally related to DMA and NMP, delays LPS-induced preterm birth in a murine model without overt toxic effects. Re-purposing the DMA/DMF/NMP family of small molecules as anti-inflammatory drugs is a promising new approach to delaying or reducing the incidence of inflammation-induced preterm birth and potentially attenuating other inflammatory disorders as well.

Original languageEnglish (US)
JournalReproductive Sciences
DOIs
StateAccepted/In press - 2022

Keywords

  • Inflammation
  • N,N-Dimethylacetamide
  • N,N-Dimethylformamide
  • Preterm Birth

ASJC Scopus subject areas

  • Obstetrics and Gynecology

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