title: N,N-dimethylacetamide regulates the proinflammatory response associated with endotoxin and prevents preterm birth.
abstract: The proinflammatory response leads to various types of pathologic pathways, including the development of preterm birth. Preterm birth occurs in 12% of deliveries in the United States and causes more than 70% of perinatal morbidity and mortality. The most common cause of spontaneous preterm birth is intrauterine infection in the mother. There is accumulating evidence indicating that the release of proinflammatory cytokines plays a critical role in the pathogenesis of inflammation-associated premature delivery. We found that the common organic solvent, N,N-dimethylacetamide (DMA), prevents endotoxin-induced preterm birth in timed pregnant C57BL/6 embryonic day (E)15.5 mice and rescues their pups from spontaneous abortion at doses many-fold lower than those currently used clinically and in a dose-dependent fashion. We also provide histologic evidence that DMA suppresses the endotoxin-triggered proinflammatory response by significantly attenuating inflammatory cell infiltration of placental tissue. Furthermore, immunoblotting analysis of placental tissue harvested from our murine models revealed DMA-mediated regulation of expression of the proinflammatory cytokines IL-1β, tumor necrosis factor α, and IL-6, and increased expression of the regulatory inflammatory cytokine IL-10. By using in vitro studies, we provide evidence that DMA suppresses macrophage function and that this small molecule prevents nuclear translocation of nuclear factor-kB. These results suggest that DMA represents a newly discovered, nontoxic therapy for a broad range of inflammatory disorders.
authors.affiliation: Department of Pharmaceutical Sciences, St. John's University, Queens, New York 11439, USA.
authors.forename: Sruthi
authors.initials: S
authors.lastname: Sundaram
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Ryan
authors.initials: R
authors.lastname: Pekson
authors.forename: Vaishali
authors.initials: V
authors.lastname: Sampat
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Sitapara
authors.forename: Lin
authors.initials: L
authors.lastname: Mantell
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Haoting
authors.initials: H
authors.lastname: Yen
authors.forename: Khushboo
authors.initials: K
authors.lastname: Abhichandani
authors.forename: Swapna
authors.initials: S
authors.lastname: Munnangi
authors.forename: Nikhil
authors.initials: N
authors.lastname: Khadtare
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Stephani
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Reznik
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000187:drug effects*; D004731:Endotoxins / Q000633:toxicity*; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000187:drug effects; D011247:Pregnancy; D047928:Premature Birth / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D000081:Acetamides; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C013959:dimethylacetamide