Neuroendocrinology · 2025
Impact of Hyperoside on the Blood-Brain Barrier in Rats with Bacterial Meningitis through the MicroRNA-155/Brain-Derived Neurotrophic Factor Pathway.
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Zhang Tao, Zhao Long, Kuang Renzhao
Аннотация
OBJECTIVE: This study aimed to elucidate the effect and mechanism of hyperoside on blood-brain barrier (BBB) damage in bacterial meningitis (BM) by regulating the microRNA-155 (miR-155)/brain-derived neurotrophic factor (BDNF) pathway.
METHODS: A rat model of meningitis was established via intracisternal injection of Streptococcus pneumoniae (SPN), while an in vitro BBB injury model was created by treating human cerebral microvascular endothelial cells (hCMEC/D3) with lipopolysaccharide (LPS). Hyperoside was administered in both models. Evans blue staining was used to assess BBB permeability in rats. Brain water content was determined using the wet-dry weight method. Transendothelial electrical resistance (TEER) was measured with an endothelial resistance meter. RT-qPCR, Western blotting, and ELISA were conducted to assess the expression of tight junction proteins (ZO-1, Claudin-5, and AQP4) in brain tissues and cell supernatants. ELISA was also used to measure inflammatory cytokines (TNF-α, IL-1β, IL-6) in cerebrospinal fluid and cell culture supernatants. Bioinformatics analysis and dual-luciferase reporter assays were employed to predict and validate the regulatory relationship between miR-155 and BDNF.
RESULTS: Hyperoside treatment reduced BBB permeability, alleviated brain edema, and suppressed inflammatory cytokine expression in SPN-infected rats. In LPS-induced hCMEC/D3 cells, hyperoside significantly increased TEER values. Furthermore, hyperoside markedly downregulated miR-155 and upregulated BDNF expression. miR-155 was confirmed to directly target BDNF and negatively regulate its expression in hCMEC/D3 cells. Importantly, the administration of a miR-155 mimic or BDNF knockdown (sh-BDNF) partially reversed the protective effects of hyperoside on TEER, tight junction protein expression (ZO-1, Claudin-5, AQP4), and inflammatory cytokine levels (TNF-α, IL-1β, IL-6) in LPS-induced hCMEC/D3 cells.
CONCLUSION: Hyperoside mitigates BBB damage in BM via reducing miR-155 expression and upregulating BDNF expression, leading to an increase in tight junction-related protein expression, a reduction in inflammatory factor secretion, and a decrease in BBB permeability.
METHODS: A rat model of meningitis was established via intracisternal injection of Streptococcus pneumoniae (SPN), while an in vitro BBB injury model was created by treating human cerebral microvascular endothelial cells (hCMEC/D3) with lipopolysaccharide (LPS). Hyperoside was administered in both models. Evans blue staining was used to assess BBB permeability in rats. Brain water content was determined using the wet-dry weight method. Transendothelial electrical resistance (TEER) was measured with an endothelial resistance meter. RT-qPCR, Western blotting, and ELISA were conducted to assess the expression of tight junction proteins (ZO-1, Claudin-5, and AQP4) in brain tissues and cell supernatants. ELISA was also used to measure inflammatory cytokines (TNF-α, IL-1β, IL-6) in cerebrospinal fluid and cell culture supernatants. Bioinformatics analysis and dual-luciferase reporter assays were employed to predict and validate the regulatory relationship between miR-155 and BDNF.
RESULTS: Hyperoside treatment reduced BBB permeability, alleviated brain edema, and suppressed inflammatory cytokine expression in SPN-infected rats. In LPS-induced hCMEC/D3 cells, hyperoside significantly increased TEER values. Furthermore, hyperoside markedly downregulated miR-155 and upregulated BDNF expression. miR-155 was confirmed to directly target BDNF and negatively regulate its expression in hCMEC/D3 cells. Importantly, the administration of a miR-155 mimic or BDNF knockdown (sh-BDNF) partially reversed the protective effects of hyperoside on TEER, tight junction protein expression (ZO-1, Claudin-5, AQP4), and inflammatory cytokine levels (TNF-α, IL-1β, IL-6) in LPS-induced hCMEC/D3 cells.
CONCLUSION: Hyperoside mitigates BBB damage in BM via reducing miR-155 expression and upregulating BDNF expression, leading to an increase in tight junction-related protein expression, a reduction in inflammatory factor secretion, and a decrease in BBB permeability.