Study on the Mechanism of Berberine Based on PI3K/mTOR/Autophagy Pathway to Ameliorate Sepsis-associated Encephalopathy Injury

Background Sepsis-associated encephalopathy (SAE) is a major cause of high mortality, and no specific therapeutic drugs are currently available. Berberine has been well-documented for its neuroprotective effects, but its mechanism of action remains unclear. Purpose Use of network pharmacology to study the mechanism of action of berberine (BER) in the treatment of sepsis-associated encephalopathy (SAE). Materials and Methods Application of network pharmacology to predict the signalling pathway of BER in the treatment of SAE. The mouse model of SAE was constructed, and determination of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-10 (IL-10) was done by enzyme-linked immunosorbent assay (ELISA). The effects of BER on neuronal damage in SAE mice were examined by haematoxylin-eosin (HE) staining and Nissl staining. Transmission electron microscopy was used to observe neuronal autophagy formation, and Western blot analysis was employed to explore the mechanism of action. Results Based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, BER is most likely to treat SAE via the phosphatidylinositol-3 kinase (PI3K)-Akt pathway. TNF-α, IL-1β, IL-6 and IL-10 levels were significantly lower in the BER group than in the SAE group, and the opposite trend was shown in the 3MA group. HE staining and Nissl staining BER were found to significantly reduce SAE injury; terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and transmission electron microscopy visualised under the microscope that the injured cells were shrunken and apoptosis occurred. Western blotting experiments revealed that PI3K, mammalian target of rapamycin (mTOR), matrix metalloprotein-9 (MMP-9) and p62 were reduced in the BER group as compared to the SAE group; Beclin1 and light chain 3 (LC3) were elevated; the opposite trend was shown in the 3MA group. Conclusion This study predicted the mechanism of action of BER acting on the PI3K/mTOR signalling pathway for the treatment of SAE and linked more potential therapeutic targets.