Hyperforin ameliorates neuroinflammation and white matter lesions by regulating microglial VEGFR₂/SRC pathway in vascular cognitive impairment mice

Aim To explore the neuroprotective potential of hyperforin and elucidate its underlying molecular mechanisms involved in its therapeutic effects against vascular cognitive impairment (VCI). Methods The active compounds and possible targets of Hypericum perforatum L. that may be effective against VCI were found by network pharmacology in this research. We utilized bilateral common carotid artery occlusion (BCCAO) surgery to induce a VCI mouse model. Morris water maze (MWM) and Y‐maze tests were used to assess VCI mice's cognitive abilities following treatment with hyperforin. To evaluate white matter lesions (WMLs), we utilized Luxol fast blue (LFB) stain and immunofluorescence (IF). Neuroinflammation was assessed using IF, western blot (WB), and enzyme‐linked immunosorbent assay (ELISA). The effects of hyperforin on microglia were investigated by subjecting the BV2 microglial cell line to oxygen–glucose deprivation/reperfusion (OGD/R) stimulation. The expressions of VEGFR 2 , p‐SRC, SRC, VEGFA, and inflammatory markers including IL‐10, IL‐1β, TNF‐α, and IL‐6 were subsequently assessed. Results The VEGFR 2 /SRC signaling pathway is essential for mediating the protective properties of hyperforin against VCI according to network pharmacology analysis. In vivo findings demonstrated that hyperforin effectively improved BCCAO‐induced cognitive impairment. Furthermore, staining results showed that hyperforin attenuated WMLs and reduced microglial activation in VCI mice. The hyperforin treatment group's ELISA results revealed a substantial decrease in IL‐1β, IL‐6, and TNF‐α levels. According to the results of in vitro experiments, hyperforin decreased the release of pro‐inflammatory mediators (TNF‐α, IL‐6, and IL‐1β) and blocked microglial M1‐polarization by modulating the VEGFR 2 /SRC signaling pathway. Conclusion Hyperforin effectively modulated microglial M1 polarization and neuroinflammation by inhibiting the VEGFR 2 /SRC signaling pathways, thereby ameliorating WMLs and cognitive impairment in VCI mice.