The FDA-approved excipient N,N-dimethylacetamide improves survival and attenuates inflammatory pathways in a murine...

Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection and remains a major public health burden. According to the Centers for Disease Control and Prevention, approximately 1.7 million adults in the United States develop sepsis annually. We previously demonstrated that the United States Food and Drug Administration-approved drug excipient N,N-dimethylacetamide (DMA) suppresses inflammatory responses through inhibition of the nuclear factor kappa B (NF-κB) pathway. In the present study, DMA completely prevented mortality in a murine model of acute (24 h) moderate endotoxemia and significantly improved survival in acute severe endotoxemia. In mice with severe endotoxemia, serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were significantly reduced in DMA-treated animals compared with lipopolysaccharide (LPS)-only controls. In long-term (96 h) moderate endotoxemia, pretreatment with DMA significantly improved clinical parameters, including mobility, heart rate, and respiratory rate. In the liver, DMA suppressed LPS-induced expression of pro-inflammatory cytokines and acute-phase proteins, enhanced expression of the anti-inflammatory cytokine IL-10, attenuated NLRP3 inflammasome activation, and modulated leukocyte infiltration in pretreated mice. In U937 macrophages, DMA inhibited LPS-induced release of IL-6 and TNF-α. Notably, macrophages differentiated in the presence of DMA exhibited an attenuated inflammatory response to subsequent LPS stimulation. Collectively, these findings identify DMA as a promising adjunctive therapeutic anti-inflammatory candidate in endotoxemia that warrants further evaluation in clinically relevant models of sepsis.