Principal Findings: In this report, using both in vitro and in vivo approaches, we show that DMF significantly decreases LPS-induced cytokine secretion from both macrophages and placental trophoblasts, cytokine expression in the placental labyrinth and immune cell infiltration at the maternal-fetal interface. Finally, we show here, for the first time, that DMF prevents inflammation-induced preterm birth and rescues pups from spontaneous abortion without producing overt toxic effects in the mother or overt teratogenic effects in the fetuses. DMF’s anti-inflammatory and tocolytic efficacies are, in fact, similar to those of DMA.21, 22
Results (in the context of what is known): Recent studies have shown that the aprotic solvents, DMA and NMP, which are structurally related to DMF, have anti-inflammatory efficacy.21–24 We were the first to show that DMA inhibits NF-κB in vitro and prevents inflammation driven PTB in an in vivo.21 In the work presented here, we show that the closely related aprotic solvent, DMF, has anti-inflammatory efficacy by decreasing the levels of the cytokines TNFα, IL-6 and IL-8 and, specifically, prevents inflammation-induced PTB in vivo.
Clinical Implications: As there are currently no FDA approved drugs to arrest preterm labor, the discovery of a new anti-inflammatory compound that prevents inflammation-driven birth is of significant clinical importance. Apart from its important effect on PTB risk, DMF’s ability to decrease the levels of inflammatory cytokines has an additional significant benefit for the fetus, namely the prevention of fetal inflammatory response syndrome, which has been associated with elevated levels of IL-6.29 The elevated IL-6 levels in inflammatory response syndrome can result in several types of injury to the developing fetal brain, including cytokine-induced periventricular leukomalacia,30 hippocampal inflammation31 and dysregulation of hippocampal glutamatergic homeostasis.31 The fact that no overt toxic effects were observed in the dams and no overt teratogenic effects were observed in the pups suggests that DMF is a promising candidate for a novel tocolytic drug. Further toxicity studies followed by clinical trials are warranted to fully assess the efficacy and safety of this molecule.
Research Implications: We and others have described various mechanisms of action of DMA and NMP, which are structurally related to DMF, including inhibition of NF-κB,21–23 inhibition of the mitogen-activated protein kinase pathway24 and inhibition of gene transcription by acting as bromodomain ligands.23, 24 The precise mechanism of action of DMF is yet to be elucidated.
Strengths and Limitations: This study has several important strengths. First, it addresses the urgent need for novel pharmacologic approaches to PTB, a serious clinical problem with no effective treatment.32–34 Second, it includes both in vitro and in vivo methods to test our hypothesis. Third, it adds to the growing body of evidence that the DMA/DMF family of aprotic solvents has anti-inflammatory properties of potential clinical importance. Fourth, it shows that DMF’s desirable anti-inflammatory properties are present at concentrations below cytotoxic levels in vitro and below toxic or teratogenic levels in vivo. A weakness of this study is that, due to IACUC restrictions, the effect of DMF on LPS-challenged mice was only followed for 24 h.
Conclusions: Inflammation has been implicated in a wide range of human disorders, including cardiovascular disease,35, 36 cancer,37–40 neurodegenerative disorders41–43 and of course PTB.11 While pharmacotherapy exists for some of these medical challenges, many clinical needs related to inflammation remain unmet. In the United States, apart from inflammation resulting from infection, sterile inflammation is driven by dietary, environmental and even social factors. In fact, we have recently shown that consumption of a high fat diet during pregnancy activates the oxidative stress/inflammatory axis8, 26 and leads to increased rates of PTB in rodent models. The DMA/DMF family of aprotic solvents may represent a novel, safe, accessible and affordable approach to treat inflammation driven preterm birth as well as other disorders resulting from inflammation for which existing drug therapy has not been fully efficacious.