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

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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.

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Data Availability

The data that support the findings in this study are available from the corresponding author upon reasonable request.

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Acknowledgments

This work was funded by a grant from the National Institutes of Health to SER (1R01NS069577). We are grateful to Helen Scaramell and the entire staff of the St. John’s University Animal Care Center for maintenance of our mouse colony and assistance with in vivo protocols. We also thank Ms. Ernestine Middleton of Montefiore Medical Center, Bronx, NY, for her expert technical support in preparing the histology slides.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, St. John’s University, Queens, NY, USA

    Zeng-Hui Wei, Oluwabukola O. Salami, Jagadish Koya, Charles R. Ashby Jr & Sandra E. Reznik

  2. Department of Surgery, Nassau University Medical Center, Nassau, NY, USA

    Swapna Munnangi

  3. Departments of Cell Biology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

    Ryan Pekson

  4. Departments of Pathology and Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, NY, USA

    Sandra E. Reznik

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  1. Zeng-Hui Wei
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Contributions

Z.-H. W. and O.O.S. performed all of the experiments and contributed equally to this manuscript. J.K. assisted in the performance of the in vitro experiments. S.M. assisted in the performance of the in vivo experiments. R.P. assisted with the statistical analyses. C.R.A. contributed to the original idea of the project and assisted with the writing of the manuscript. S.E.R. contributed to the original idea of the project, wrote the manuscript and provided funding.

Corresponding author

Correspondence to Sandra E. Reznik.

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Approval was obtained from the St. John’s University IACUC, assurance number D16-00346 (A3574-01).

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Supplemental Figure 1.

DMF’s effect on cell viability. A, RAW 264.7 cells and B, HTR-8 cells were incubated with or without concentrations of DMF ranging from 0.1 to 40 mM. Cell viability was assessed using the MTT assay. The double asterisks indicate P<0.01 and the quadruple asterisks indicate P<.0001, as compared to the control group. HTR-8, HTR-8/SVNeo; DMF, N,N-dimethylformamide; LPS, lipopolysaccharide; MTT, 3-(4,5-dimethyl thiazolyl-2)-2,5-diphenyl tetrazolium bromide. (DOCX 3647 kb)

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Wei, ZH., Salami, O.O., Koya, J. et al. N,N-Dimethylformamide Delays LPS-Induced Preterm Birth in a Murine Model by Suppressing the Inflammatory Response. Reprod. Sci. 29, 2894–2907 (2022). https://doi.org/10.1007/s43032-022-00924-z

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