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We utilized bilateral common carotid artery occlusion (BCCAO) surgery to induce a VCI mouse model. Morris water maze (MWM) and Y\u2010maze 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\u2010linked immunosorbent assay (ELISA). The effects of hyperforin on microglia were investigated by subjecting the BV2 microglial cell line to oxygen\u2013glucose deprivation\/reperfusion (OGD\/R) stimulation. The expressions of VEGFR<jats:sub>2<\/jats:sub>, p\u2010SRC, SRC, VEGFA, and inflammatory markers including IL\u201010, IL\u20101\u03b2, TNF\u2010\u03b1, and IL\u20106 were subsequently assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The VEGFR<jats:sub>2<\/jats:sub>\/SRC signaling pathway is essential for mediating the protective properties of hyperforin against VCI according to network pharmacology analysis. In\u00a0vivo findings demonstrated that hyperforin effectively improved BCCAO\u2010induced 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\u20101\u03b2, IL\u20106, and TNF\u2010\u03b1 levels. According to the results of in\u00a0vitro experiments, hyperforin decreased the release of pro\u2010inflammatory mediators (TNF\u2010\u03b1, IL\u20106, and IL\u20101\u03b2) and blocked microglial M1\u2010polarization by modulating the VEGFR<jats:sub>2<\/jats:sub>\/SRC signaling pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Hyperforin effectively modulated microglial M1 polarization and neuroinflammation by inhibiting the VEGFR<jats:sub>2<\/jats:sub>\/SRC signaling pathways, thereby ameliorating WMLs and cognitive impairment in VCI mice.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14666","type":"journal-article","created":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T04:19:56Z","timestamp":1710217196000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Hyperforin ameliorates neuroinflammation and white matter lesions by regulating microglial 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