Shenghui Decoction ameliorates cognitive impairment and neuroinflammation in APP/PS1 mice via modulation of the HMGB1/TLR4/NLRP3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenghui Decoction (SHD), a traditional Chinese medicinal formula, has previously been reported to alleviate neuroinflammation and improve the cognitive deficits associated with Alzheimer's disease (AD). However, the molecular mechanisms responsible for these protective effects remain incompletely understood. AIM OF THE STUDY: This study aimed to investigate the effects of SHD on cognitive dysfunction and neuroinflammation in APP/PS1 mice and to explore its relationship with the HMGB1/TLR4/NLRP3 signaling pathway. MATERIALS AND METHODS: Male APP/PS1 transgenic mice served as the animal model in this study. The Y-maze and Morris water maze (MWM) were used to evaluate cognitive performance. Histopathological alterations in the hippocampus were assessed by hematoxylin and eosin (H&E) staining, and astrocyte activation was evaluated by GFAP immunofluorescence staining. The changes in HMGB1 activation status were evaluated by HMGB1 immunofluorescence staining, and the NLRP3 inflammatory signaling level in Aβ deposition areas was detected by double immunofluorescence staining for Aβ and NLRP3. Protein levels of HMGB1, TLR4, NLRP3, NF-κB p65, IL-6, and IL-1β were further analyzed by Western blotting. RESULTS: A total of 30 representative compounds were identified from the SHD extract. Behavioral assessments indicated that SHD improved behavioral performance in APP/PS1 mice. H&E staining revealed that SHD attenuated neuronal pathological damage in the hippocampal CA1 region. Immunofluorescence analysis showed that SHD reduced astrocyte activation, improved abnormal HMGB1 activation status, and decreased NLRP3 inflammatory signaling levels in Aβ deposition areas. Consistently, Western blot results demonstrated that SHD markedly reduced the protein levels of HMGB1, TLR4, NLRP3, NF-κB p65, IL-6, and IL-1β. CONCLUSION: SHD improved cognitive dysfunction and alleviated neuroinflammation in APP/PS1 mice. Its neuroprotective effects may be associated with the regulation of the HMGB1/TLR4/NLRP3 signaling pathway.