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

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.