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: Sruthi Sundaram, Charles R Ashby Jr, Ryan Pekson, Vaishali Sampat, Ravikumar Sitapara, Lin Mantell, Chih-Hung Chen, Haoting Yen, Khushboo Abhichandani, Swapna Munnangi, Nikhil Khadtare, Ralph A Stephani, Sandra E Reznik
• Journal: The American journal of pathology (Am J Pathol) Vol. 183 Issue 2 Pg. 422-30 (Aug 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23770347 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Acetamides
• Anti-Inflammatory Agents
• Cytokines
• Endotoxins
• Lipopolysaccharides
• NF-kappa B
• dimethylacetamide

Topics

• Acetamides (pharmacology)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cytokines (drug effects)
• Endotoxins (toxicity)
• Female
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (drug effects)
• Pregnancy
• Premature Birth (chemically induced, prevention & control)