Angelicin alleviates sepsis-associated encephalopathy via inhibition of IKK2 and the NF-κB pathway

Sepsis-associated encephalopathy (SAE) is a critical neurological complication in patients with sepsis and is pathologically characterized by neuroinflammation, blood-brain barrier (BBB) damage and neurobehavioral dysfunction but remains therapeutically challenging because of the lack of targeted treatment options.

The objective of this study was to explore the protective effects of angelicin (ANG) against cecal ligation and puncture (CLP)-induced SAE in mice, particularly its ability to mitigate neuroinflammation, BBB damage, and neurobehavioural dysfunction, and to investigate the underlying mechanisms involved.

A total of 168 mice were randomly divided into 7 groups: a sham-operated group (sham), a sham-treated group (sham + 10 mg/kg ANG), a CLP group, an angelicin low-dose group (CLP + 2.5 mg/kg ANG), an angelicin medium-dose group (CLP + 5 mg/kg ANG), an angelicin high-dose group (CLP + 10 mg/kg ANG) and a positive control group (CLP + DEX). A variety of experimental methods, including HE staining, Nissl staining, Evans blue staining, quantitative real-time PCR, western blotting, and behavioral trials, were used to evaluate the biological processes of neuroinflammation, the BBB, and neurobehavioral dysfunction in SAE.

ANG alleviated pathological changes in CLP-induced SAE (as indicated by preserved hippocampal structural integrity and elevated Nissl body density), neurobehavioral dysfunction (as indicated by significantly increased exploration time for new objects, recognition index, spontaneous alternation rate, and time spent exploring the target quadrant of the water maze), BBB damage (as indicated by reduced fluorescence intensity of Evans blue leakage, decreased levels of S100β and NSE secretion, increased levels of tight junction protein transcripts, and protein expression), and the inflammatory response (as indicated by reduced levels of the proinflammatory factors Il-1β, Il-6, and Tnf-α, and increased levels of the anti-inflammatory factor Il-10). Transcriptome analysis revealed that the NF-κB signaling pathway was significantly altered following ANG treatment. Further molecular docking, SPR, cell transfection, and inhibitor intervention experiments demonstrated that ANG ameliorated neuroinflammation in SAE by inhibiting IKK2.

ANG mitigated neuroinflammation, BBB damage, and neurobehavioral dysfunction in CLP-induced SAE mice by specifically inhibiting IKK2 activity and suppressing NF-κB signaling pathway activation, suggesting that ANG is a promising therapeutic candidate for SAE treatment.