Abstract
Chronic cerebral hypoperfusion (CCH) is a major contributor to vascular dementia, with neuroinflammation playing a central role in its pathogenesis. Sinomenine (SINO), a natural alkaloid derived from traditional Chinese medicine, has shown significant anti-inflammatory and neuroprotective properties. However, its efficacy and mechanism of action in CCH remain unclear. In this study, we established a CCH rat model through bilateral common carotid artery occlusion and administered 10 mg/kg of SINO daily. Behavioral tests demonstrated that SINO significantly improved cognitive and memory functions in CCH rats. Histological analysis revealed that SINO effectively reduced neuroinflammation and damage in the hippocampal CA1, CA3, and DG regions. Mechanistically, SINO promoted microglial polarization from the M1 to M2 phenotype, markedly inhibiting the release of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Further exploration of its neuroprotective mechanism showed that exosomes from SINO-treated microglia were enriched with miRNA-223-3p, which suppressed NLRP3-mediated pyroptosis in neurons. While our findings highlight the therapeutic potential of SINO, further studies are needed to validate its safety and efficacy in diverse populations and chronic settings. In summary, this study not only demonstrates SINO's regulatory effect on microglial polarization in CCH but also unveils a novel neuroprotective mechanism through exosomal miRNA-223-3p delivery, providing a solid theoretical foundation for SINO's potential as a treatment for CCH.