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A novel paracetamol derivative alleviates lipopolysaccharide-induced neuroinflammation

Year: 2025

Type: article

Abstract: Neuroinflammation has been implicated as a pathological contributor to several neurodegenerative disorders. Increasing evidence suggests that paracetamol (PCM, acetaminophen) has unappreciated anti-neuroinflammatory properties. However, PCM possesses hepatotoxicity in higher dosages, which are needed for achieving therapeutic concentrations in the brain. To lessen this effect and improve drug efficacy, PCM was in this study converted into an L-type amino acid transporter 1 (LAT1)-utilizing derivative and tested whether this LAT1-mediated delivery approach could enhance the relief of neuroinflammation, using both in vitro and in vivo lipopolysaccharide (LPS)-stimulated models. The gained results confirmed the derivative's improved transport into mouse primary astrocytes, immortalized microglia (BV2), and human immortalized microglia (SV40) via LAT1. In the LPS-stimulated BV2 model, the derivative effectively reduced the prostaglandin E 2 (PGE 2 ) level by 57% compared to the LPS treatment. Moreover, a more profound reduction of brain PGE 2 production was confirmed in the LPS-stimulated mouse model. Finally, the global proteome of the whole mouse brain revealed that the derivative was able to reverse the altered expression of several inflammatory biomarkers, including ras-related C3 botulinum toxin substrate 1 ( Rac1 ), cytochrome c oxidase subunit 2 ( COX2 ), phospholipid phosphatase-related protein type 2 ( Plppr2 ), ubiquitin-conjugating enzyme E2 variant 1 ( Ube2v1 ) and A-kinase anchor protein 1, mitochondrial ( Akap1 ). • Transporter-utilizing compound of paracetamol was synthetized and characterized. • The uptake into brain cells was increased significantly compared to paracetamol. • The compound reduced prostaglandin E 2 production in vitro and in the mouse brain. • The compound reversed the altered expression of several inflammatory biomarkers. • Therefore, the compound can improve the neuroprotective activity of paracetamol.

Source: European Journal of Pharmacology

DOI: 10.1016/j.ejphar.2025.177409