Ruan Qingwei, Hu Xiaona, Ao Huafei, Ma Haifeng, Gao Zhanjuan, Liu Fang, Kong Deqiu, Bao Zhijun, Yu Zhuowei
Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Medical College, Fudan University, Shanghai, PR China.
Gerontology. 2014;60(5):424-39. doi: 10.1159/000358235. Epub 2014 Jun 21.
Chronic administration of D-galactose (D-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 D-gal-induced neurovascular damage, as well as the protective effects of huperzine A.
The purpose of this study was to utilize a D-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 D-gal-induced neuronal and vascular inflammatory injury.
Aging rats were treated with D-gal (300 mg/kg s.c. for 8 weeks), were coadministered D-gal and huperzine A (D-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.
Our study revealed that chronic administration of D-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 D-gal-induced increase in acetylcholinesterase (AChE) activity, but also alleviated D-gal-induced neurovascular damage by inhibiting D-gal-induced NF-κB activation, improving cerebrovascular function and suppressing the D-gal-induced decrease in the density and protein levels of TJs and cell apoptosis.
Our findings provided evidence that D-gal induced a proinflammatory phenotype mediated by NF-κB in the rat hippocampus. Moreover, huperzine A suppressed D-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 D-gal-induced inflammatory damage.
长期给予D-半乳糖（D-gal）会导致氧化应激和慢性炎症性衰老。大脑中与年龄相关的变化会导致神经血管损伤和血脑屏障（BBB）功能障碍。然而，关于D-半乳糖诱导的神经血管损伤以及石杉碱甲的保护作用，人们了解甚少。
本研究旨在利用D-半乳糖诱导的大鼠模型，研究大鼠海马体中神经血管炎性损伤和细胞凋亡的激活情况，并了解石杉碱甲是否能减轻D-半乳糖诱导的神经元和血管炎性损伤。
将衰老大鼠用D-半乳糖（300mg/kg皮下注射，持续8周）处理，同时给予D-半乳糖和石杉碱甲（D-半乳糖300mg/kg，石杉碱甲0.1mg/kg皮下注射，持续8周），或作为生理盐水处理的对照组大鼠（皮下注射相同体积的生理盐水，持续8周）。分析海马体形态变化和炎性损伤生物标志物。
我们的研究表明，长期给予D-半乳糖会导致胶质细胞和血管内皮细胞激活，以及通过核因子（NF）-κB抑制剂降解和NF-κB核转位，使细胞相关黏附分子和炎性细胞因子的mRNA和蛋白质水平上调。炎性损伤导致大鼠海马体中血脑屏障功能显著障碍、紧密连接（TJ）密度降低和细胞凋亡。同时给予石杉碱甲不仅显著抑制了D-半乳糖诱导的乙酰胆碱酯酶（AChE）活性增加，还通过抑制D-半乳糖诱导的NF-κB激活、改善脑血管功能以及抑制D-半乳糖诱导的TJ密度和蛋白质水平降低及细胞凋亡，减轻了D-半乳糖诱导的神经血管损伤。
我们的研究结果表明，D-半乳糖在大鼠海马体中诱导了由NF-κB介导的促炎表型。此外，石杉碱甲抑制了D-半乳糖诱导的神经血管损伤和血脑屏障功能障碍，部分原因是阻止了NF-κB核转位。石杉碱甲对AChE活性的抑制作用可能在减轻D-半乳糖诱导的炎性损伤中起重要作用。
