Journal of ethnopharmacology · 2026
Nao-Xin-Tong Capsule alleviates astrocyte end-foot swelling after cerebral ischemia-reperfusion injury via NF-κB/MMP9/AQP4 signal and NF-κB/CXCL12/CXCR4 signal.
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Shang Jinfeng, Wei Wanting, Wang Bohong, Wei Ran, Cui Yiran, Wang Jingjuan, Liu Xin
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Nao-Xin-Tong Capsule (NXT), a modern formulation derived from the classical qi-invigorating and blood-activating prescription Buyang Huanwu Decoction, has been clinically applied for ischemic stroke (IS) management over three decades with established safety. Its multi-component composition targets the core pathogenesis of cerebral no-reflow phenomenon-qi deficiency and blood stasis-by restoring microcirculatory perfusion.
AIM OF THE STUDY: This study aims to investigate the mechanistic role of NXT in mitigating astrocyte end-foot swelling during cerebral ischemia-reperfusion injury (CIRI) through modulation of the nuclear factor kappa-B (NF-κB)/matrix metalloproteinase-9 (MMP9)/aquaporin-4 (AQP4) and NF-κB/C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 4 (CXCR4) signals.
MATERIALS AND METHODS: Transient middle cerebral artery occlusion (tMCAO) rats were treated with NXT (55 mg/kg, 110 mg/kg, 220 mg/kg) or Ginaton (positive control drug, 21.6 mg/kg). U251 MG cells (astrocytes) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) received NXT-containing serum (0.5%, 1%, 2%) or edaravone (6 μM). Outcomes included cerebral blood flow (CBF), neurological deficit, cerebral edema, infarct volume (TTC staining) histopathology (HE/Nissl staining), and K+, Glu and inflammatory factor content. Transcriptomics was applied to screen for vital pathways. NF-κB pathway involvement was validated using PMA (NF-κB activator) and PS-341 (NF-κB inhibitor). Protein/mRNA expression levels of NF-κB, MMP9, AQP4, CXCL12 and CXCR4 were quantified via Western blot, RT-qPCR and immunofluorescence. HPLC was used to detect calycosin-7-glucoside and salvianolic acid B for the quality control of NXT.
RESULTS: NXT dose-dependently ameliorated CIRI by improving cerebral perfusion, reducing edema and infarction in tMCAO rats. NXT attenuated astrocyte end-foot swelling via suppressing NF-κB p65 nuclear translocation, downstream MMP9 expression, AQP4 depolarization, and NF-κB-driven CXCL12/CXCR4 activation, finally reducing neuroinflammation and vascular hyperpermeability. The medium dose of NXT had the best effect. In CIRI, NXT worked in synergy with PS-341 (NF-κB inhibitor) to exert its efficacy and reversed the damaging effects of PMA (NF-κB activator).
CONCLUSION: NXT alleviates post-ischemic no-reflow phenomenon by resolving astrocyte end-foot swelling through coordinated inhibition of NF-κB-mediated MMP9/AQP4 dysregulation and CXCL12/CXCR4 neuroinflammation. This validates its traditional "qi-invigorating and blood-activating" mechanism and positions NXT as a multi-target therapeutic strategy for CIRI.
AIM OF THE STUDY: This study aims to investigate the mechanistic role of NXT in mitigating astrocyte end-foot swelling during cerebral ischemia-reperfusion injury (CIRI) through modulation of the nuclear factor kappa-B (NF-κB)/matrix metalloproteinase-9 (MMP9)/aquaporin-4 (AQP4) and NF-κB/C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 4 (CXCR4) signals.
MATERIALS AND METHODS: Transient middle cerebral artery occlusion (tMCAO) rats were treated with NXT (55 mg/kg, 110 mg/kg, 220 mg/kg) or Ginaton (positive control drug, 21.6 mg/kg). U251 MG cells (astrocytes) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) received NXT-containing serum (0.5%, 1%, 2%) or edaravone (6 μM). Outcomes included cerebral blood flow (CBF), neurological deficit, cerebral edema, infarct volume (TTC staining) histopathology (HE/Nissl staining), and K+, Glu and inflammatory factor content. Transcriptomics was applied to screen for vital pathways. NF-κB pathway involvement was validated using PMA (NF-κB activator) and PS-341 (NF-κB inhibitor). Protein/mRNA expression levels of NF-κB, MMP9, AQP4, CXCL12 and CXCR4 were quantified via Western blot, RT-qPCR and immunofluorescence. HPLC was used to detect calycosin-7-glucoside and salvianolic acid B for the quality control of NXT.
RESULTS: NXT dose-dependently ameliorated CIRI by improving cerebral perfusion, reducing edema and infarction in tMCAO rats. NXT attenuated astrocyte end-foot swelling via suppressing NF-κB p65 nuclear translocation, downstream MMP9 expression, AQP4 depolarization, and NF-κB-driven CXCL12/CXCR4 activation, finally reducing neuroinflammation and vascular hyperpermeability. The medium dose of NXT had the best effect. In CIRI, NXT worked in synergy with PS-341 (NF-κB inhibitor) to exert its efficacy and reversed the damaging effects of PMA (NF-κB activator).
CONCLUSION: NXT alleviates post-ischemic no-reflow phenomenon by resolving astrocyte end-foot swelling through coordinated inhibition of NF-κB-mediated MMP9/AQP4 dysregulation and CXCL12/CXCR4 neuroinflammation. This validates its traditional "qi-invigorating and blood-activating" mechanism and positions NXT as a multi-target therapeutic strategy for CIRI.