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Hyperforin ameliorates neuroinflammation and white matter lesions by regulating microglial VEGFR2 /SRC pathway in
Xin Gao1, Jingjing Chen1, Ge Yin1
1Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China.
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 VEGFR2 , p-SRC, SRC, VEGFA, and inflammatory markers including IL-10, IL-1β, TNF-α, and IL-6 were subsequently assessed.
Results:
The VEGFR2 /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 VEGFR2 /SRC signaling pathway.
Conclusion:
Hyperforin effectively modulated microglial M1 polarization and neuroinflammation by inhibiting the VEGFR2 /SRC signaling pathways, thereby ameliorating WMLs and cognitive impairment in VCI mice.
Insights
Hyperforin, a compound from St. John's Wort, shows neuroprotective effects against vascular cognitive impairment (VCI) by reducing neuroinflammation and white matter lesions.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Vascular cognitive impairment (VCI) is a significant health concern.
- Hypericum perforatum L. (St. John's Wort) contains active compounds with potential therapeutic benefits.
- Network pharmacology identified hyperforin as a potential agent against VCI.
Purpose of the Study:
- To investigate the neuroprotective potential of hyperforin against VCI.
- To elucidate the molecular mechanisms underlying hyperforin's therapeutic effects in VCI.
- To evaluate hyperforin's impact on cognitive function, white matter lesions, and neuroinflammation.
Main Methods:
- A VCI mouse model was induced using bilateral common carotid artery occlusion (BCCAO).
- Cognitive function was assessed using Morris water maze and Y-maze tests.
- White matter lesions, microglial activation, and neuroinflammation markers were evaluated using Luxol fast blue staining, immunofluorescence, western blot, and ELISA.
- In vitro studies used BV2 microglial cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R).
Main Results:
- Hyperforin treatment significantly improved cognitive function in VCI mice.
- Hyperforin attenuated white matter lesions and reduced microglial activation.
- Hyperforin decreased levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in vivo and in vitro.
- Network pharmacology and in vitro results indicated the VEGFR2/SRC signaling pathway is crucial for hyperforin's effects.
Conclusions:
- Hyperforin demonstrates significant neuroprotective effects against VCI.
- Hyperforin ameliorates VCI by modulating microglial M1 polarization and neuroinflammation.
- Inhibition of the VEGFR2/SRC signaling pathway is a key mechanism for hyperforin's therapeutic action in VCI.
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