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1.
Sci Rep ; 13(1): 7077, 2023 05 01.
Article in English | MEDLINE | ID: mdl-37127686

ABSTRACT

Alzheimer's disease (AD) is a chronic degenerative brain disorder with no clear pathogenesis or effective cure, accounting for 60-80% of cases of dementia. In recent years, the importance of neuroinflammation in the pathogenesis of AD and other neurodegenerative disorders has come into focus. Previously, we made the serendipitous discovery that the widely used drug excipient N,N-dimethylacetamide (DMA) attenuates endotoxin-induced inflammatory responses in vivo. In the current work, we investigate the effect of DMA on neuroinflammation and its mechanism of action in in-vitro and ex-vivo models of AD. We show that DMA significantly suppresses the production of inflammatory mediators, such as reactive oxygen species (ROS), nitric oxide (NO) and various cytokines and chemokines, as well as amyloid-ß (Aß), in cultured microglia and organotypic hippocampal slices induced by lipopolysaccharide (LPS). We also demonstrate that DMA inhibits Aß-induced inflammation. Finally, we show that the mechanism of DMA's effect on neuroinflammation is inhibition of the nuclear factor kappa-B (NF-κB) signaling pathway and we show how DMA dismantles the positive feedback loop between NF-κB and Aß synthesis. Taken together, our findings suggest that DMA, a generally regarded as safe compound that crosses the blood brain barrier, should be further investigated as a potential therapy for Alzheimer's disease and neuroinflammatory disorders.


Subject(s)
Alzheimer Disease , Humans , NF-kappa B/metabolism , Neuroinflammatory Diseases , Signal Transduction , Amyloid beta-Peptides/metabolism
2.
Reprod Sci ; 29(10): 2894-2907, 2022 10.
Article in English | MEDLINE | ID: mdl-35349119

ABSTRACT

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.


Subject(s)
Dimethylformamide , Premature Birth , Acetamides , Animals , Anti-Inflammatory Agents/pharmacology , Dimethylformamide/adverse effects , Disease Models, Animal , Excipients/adverse effects , Female , Humans , Infant, Newborn , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/prevention & control , Interleukin-6 , Interleukin-8 , Lipopolysaccharides/pharmacology , Mice , NF-KappaB Inhibitor alpha , NF-kappa B/metabolism , Placenta/metabolism , Pregnancy , Premature Birth/chemically induced , Premature Birth/prevention & control , Solvents/adverse effects , Tumor Necrosis Factor-alpha
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