Abstract
Background: Chronic administration of <smlcap>D</smlcap>-galactose (<smlcap>D</smlcap>-gal) results in oxidative stress and chronic inflammatory aging. Age-related changes in the brain result in neurovascular damage and blood-brain barrier (BBB) dysfunction. However, little is known regarding <smlcap>D</smlcap>-gal-induced neurovascular damage, as well as the protective effects of huperzine A. Objective: The purpose of this study was to utilize a<smlcap> D</smlcap>-gal-induced rat model to investigate the activation of neurovascular inflammatory damage and apoptosis in the rat hippocampus and to understand whether huperzine A alleviates <smlcap>D</smlcap>-gal-induced neuronal and vascular inflammatory injury. Methods: Aging rats were treated with <smlcap>D</smlcap>-gal (300 mg/kg s.c. for 8 weeks), were coadministered <smlcap>D</smlcap>-gal and huperzine A (<smlcap>D</smlcap>-gal 300 mg/kg and huperzine A 0.1 mg/kg s.c. for 8 weeks) or served as the saline-treated control group rats (same volume of saline given subcutaneously for 8 weeks). Changes in hippocampal morphology and biomarkers of inflammatory damage were analyzed. Results: Our study revealed that chronic administration of <smlcap>D</smlcap>-gal resulted in the activation of glia and vascular endothelial cells and upregulation of mRNA and protein levels of cell-associated adhesion molecules and inflammatory cytokines via nuclear factor (NF)-κB inhibitor degradation and NF-κB nuclear translocation. The inflammatory injury caused significant BBB dysfunction, decreased density of tight junctions (TJs) and apoptosis in the rat hippocampus. Coadministration of huperzine A not only markedly inhibited the <smlcap>D</smlcap>-gal-induced increase in acetylcholinesterase (AChE) activity, but also alleviated <smlcap>D</smlcap>-gal-induced neurovascular damage by inhibiting <smlcap>D</smlcap>-gal-induced NF-κB activation, improving cerebrovascular function and suppressing the <smlcap>D</smlcap>-gal-induced decrease in the density and protein levels of TJs and cell apoptosis. Conclusions: Our findings provided evidence that <smlcap>D</smlcap>-gal induced a proinflammatory phenotype mediated by NF-κB in the rat hippocampus. Moreover, huperzine A suppressed <smlcap>D</smlcap>-gal-induced neurovascular damage and BBB dysfunction, partly by preventing NF-κB nuclear translocation. The inhibiting effect of huperzine A on AChE activity might play an important role in attenuating <smlcap>D</smlcap>-gal-induced inflammatory damage.
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