Neuropharmacology · 2026
Rosuvastatin attenuates blood-brain barrier dysfunction after ICH through modulation of CXCL12-associated VEGFR2/p38 MAPK signaling.
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Yuan Min, Zhou Huangyan, Pan Haili, Xiao Zhilong, Wu Hanjun, Wu Wei
Аннотация
BACKGROUND: Blood-brain barrier (BBB) disruption is a major driver of secondary injury after intracerebral hemorrhage (ICH), yet no approved therapy specifically targets post-ICH BBB damage. Rosuvastatin has pleiotropic vascular protective actions beyond lipid lowering, but its role in hemorrhagic BBB injury remains unclear. This study examined whether rosuvastatin attenuates BBB dysfunction after ICH and explored involvement of CXCL12-associated VEGFR2/p38 MAPK signaling.
METHODS: ICH was induced in rats by autologous blood injection, followed by daily rosuvastatin for 7 days. Neurological deficits, Evans blue leakage, inflammatory markers, CXCL12 localization, and BBB-related proteins were assessed in vivo. Hemin-injured hCMEC/D3 cells were used to evaluate endothelial viability, migration, tight-junction expression, and signaling changes. CXCL12 siRNA was applied to determine pathway involvement.
RESULTS: Rosuvastatin significantly improved neurological outcomes and reduced Evans blue extravasation after ICH. It lowered serum and brain IL-6 and TNF-α levels, reduced perihematomal microglial activation, restored Occludin and ZO-1 expression, and modulated ICAM-1 and p38 MAPK signaling in perihematomal tissue. CXCL12/CD31 co-localization in perihematomal vasculature increased after ICH and was attenuated by rosuvastatin. In hemin-exposed hCMEC/D3 cells, rosuvastatin improved viability and migration, restored tight-junction protein expression, and modulated CXCL12 together with changes in VEGFR2 and p38 MAPK signaling. CXCL12 silencing partially attenuated rosuvastatin's protective effects.
CONCLUSIONS: Rosuvastatin attenuates BBB dysfunction and neuroinflammatory injury after ICH and improves endothelial injury responses in vitro. These protective effects were associated, partly, with restoration of dysregulated CXCL12-associated VEGFR2/p38 MAPK signaling, highlighting the therapeutic potential of rosuvastatin for neurovascular protection after hemorrhagic stroke.
METHODS: ICH was induced in rats by autologous blood injection, followed by daily rosuvastatin for 7 days. Neurological deficits, Evans blue leakage, inflammatory markers, CXCL12 localization, and BBB-related proteins were assessed in vivo. Hemin-injured hCMEC/D3 cells were used to evaluate endothelial viability, migration, tight-junction expression, and signaling changes. CXCL12 siRNA was applied to determine pathway involvement.
RESULTS: Rosuvastatin significantly improved neurological outcomes and reduced Evans blue extravasation after ICH. It lowered serum and brain IL-6 and TNF-α levels, reduced perihematomal microglial activation, restored Occludin and ZO-1 expression, and modulated ICAM-1 and p38 MAPK signaling in perihematomal tissue. CXCL12/CD31 co-localization in perihematomal vasculature increased after ICH and was attenuated by rosuvastatin. In hemin-exposed hCMEC/D3 cells, rosuvastatin improved viability and migration, restored tight-junction protein expression, and modulated CXCL12 together with changes in VEGFR2 and p38 MAPK signaling. CXCL12 silencing partially attenuated rosuvastatin's protective effects.
CONCLUSIONS: Rosuvastatin attenuates BBB dysfunction and neuroinflammatory injury after ICH and improves endothelial injury responses in vitro. These protective effects were associated, partly, with restoration of dysregulated CXCL12-associated VEGFR2/p38 MAPK signaling, highlighting the therapeutic potential of rosuvastatin for neurovascular protection after hemorrhagic stroke.