TY - JOUR
T1 - N,N-Dimethylformamide Delays LPS-Induced Preterm Birth in a Murine Model by Suppressing the Inflammatory Response
AU - Wei, Zeng Hui
AU - Salami, Oluwabukola O.
AU - Koya, Jagadish
AU - Munnangi, Swapna
AU - Pekson, Ryan
AU - Ashby, Charles R.
AU - Reznik, Sandra E.
N1 - Funding Information:
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.
Publisher Copyright:
© 2022, Society for Reproductive Investigation.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Inflammation
KW - N,N-Dimethylacetamide
KW - N,N-Dimethylformamide
KW - Preterm Birth
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U2 - 10.1007/s43032-022-00924-z
DO - 10.1007/s43032-022-00924-z
M3 - Article
C2 - 35349119
AN - SCOPUS:85127279151
JO - Reproductive Sciences
JF - Reproductive Sciences
SN - 1933-7191
ER -