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N,N Dimethylacetamide attenuates LPS induced neuroinflammation in a murine model

ABSTRACT: Neuroinflammation is a central driver of cognitive decline in many neurodegenerative diseases and is marked by persistent activation of pro-inflammatory pathways. N,N-Dimethylacetamide (DMA), an FDA-approved excipient with emerging anti-inflammatory properties, was evaluated for its therapeutic potential in a murine model of chronic neuroinflammation. Both male and female C57BL/6 mice were administered lipopolysaccharide (LPS; 0.5 mg/kg) to induce neuroinflammation over seven days, followed by treatment with DMA. Behavioral assays—including the Radial Arm Maze and Novel Object Recognition tests—revealed significant cognitive deficits in LPS-treated animals, which were attenuated in DMA-treated mice, indicating preserved spatial memory and object recognition. To elucidate underlying molecular changes, RNA sequencing was performed on brain tissue, and differential gene expression analysis was followed by KEGG pathway enrichment. LPS exposure upregulated pathways related to immune activation, including TNF signaling, NF-κB signaling, MAPK signaling, and cytokine–cytokine receptor interactions. DMA treatment reversed many of these transcriptional changes, downregulating pro-inflammatory signaling and upregulating genes involved in neuroprotection and synaptic signaling. These findings suggest that DMA not only modulates key inflammatory pathways at the transcriptomic level but also improves cognitive function in a neuroinflammatory context. Collectively, this study highlights DMA’s potential as a therapeutic agent for preventing inflammation-associated cognitive decline.

ORGANISM(S): Mus musculus

PROVIDER: GSE304500 | GEO | 2026/02/17

REPOSITORIES: GEO

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Project description:Acute cognitive impairment (i.e., delirium) is common in elderly emergency department patients and frequently results from infections that are unrelated to the central nervous system. Since activation of the peripheral innate immune system induces brain microglia to produce inflammatory cytokines that are responsible for behavioral deficits, we investigated if aging exacerbated neuroinflammation and sickness behavior after peripheral injection of lipopolysaccharide (LPS). Microarray analysis revealed a transcriptional profile indicating the presence of primed or activated microglia and increased inflammation in the aged brain. Furthermore, aged mice had a unique gene expression profile in the brain after an intraperitoneal injection of LPS, and the LPS-induced elevation in the brain inflammatory cytokines and oxidative stress was both exaggerated and prolonged compared with adults. Aged mice were anorectic longer and lost more weight than adults after peripheral LPS administration. Moreover, reductions in both locomotor and social behavior remained 24 h later in aged mice, when adults had fully recovered, and the exaggerated neuroinflammatory response in aged mice was not reliably paralleled by increased circulating cytokines in the periphery. Taken together these data establish that activation of the peripheral innate immune system leads to exacerbated neuroinflammation in the aged as compared with adult mice. This dysregulated link between the peripheral and central innate immune system is likely to be involved in the severe behavioral deficits that frequently occur in older adults with systemic infections. Experiment Overall Design: In this study, adult and aged mice were injected intraperitoneal with sterile saline or Escherichia coli LPS (0.33 mg/kg, ~10 µg/mouse; serotype 0127:B8, Sigma). This dosage of LPS was used because it induces a mild transient sickness behavior in young adults. Mice were killed 4 h after saline or LPS injection by CO2 asphyxiation. Blood samples were collected and brains were removed, separated in half at the longitudinal fissure, frozen in liquid nitrogen, and stored (-80°C) until assaying. Total RNA was later isolated from some brain samples for microarray analysis (n=3).

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N,N Dimethylacetamide attenuates LPS induced neuroinflammation in a murine model

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