World Class University Biomodulation Program, Department of Agricultural Biotechnology, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-921, Republic of Korea.
J Pharmacol Exp Ther. 2011 Jun;337(3):747-54. doi: 10.1124/jpet.110.176925. Epub 2011 Mar 11.
Kaempferol, a natural flavonoid isolated from various plant sources, has been identified as a potential neuroprotectant. In this study, we investigated the protective effect of kaempferol against 4-hydroxynonenal (HNE)-induced apoptosis in PC12 rat pheochromocytoma cells. Kaempferol inhibited 4-HNE-mediated apoptosis, characterized by nuclear condensation, down-regulation of antiapoptotic protein Bcl-2, and activation of proapoptotic caspase-3. Kaempferol inhibited 4-HNE-induced phosphorylation of c-Jun N-terminal protein kinase (JNK). More importantly, kaempferol directly bound p47(phox), a cytosolic subunit of NADPH oxidase (NOX), and significantly inhibited 4-HNE-induced activation of NOX. The antiapoptotic effects of kaempferol were replicated by the NOX inhibitor apocynin, suggesting that NOX is an important enzyme in its effects. Our results suggest that kaempferol attenuates 4-HNE-induced activation of JNK and apoptosis by binding p47(phox) of NOX and potently inhibiting activation of the NOX-JNK signaling pathway in neuron-like cells. Altogether, these results suggest that kaempferol may be a potent prophylactic against NOX-mediated neurodegeneration.
山柰酚是一种从各种植物来源中分离出来的天然类黄酮，已被鉴定为一种有潜力的神经保护剂。在这项研究中，我们研究了山柰酚对 4-羟壬烯醛（HNE）诱导的 PC12 大鼠嗜铬细胞瘤细胞凋亡的保护作用。山柰酚抑制了 4-HNE 介导的凋亡，其特征为核浓缩、抗凋亡蛋白 Bcl-2 的下调以及促凋亡 caspase-3 的激活。山柰酚抑制了 4-HNE 诱导的 c-Jun N 末端蛋白激酶（JNK）的磷酸化。更重要的是，山柰酚直接结合 NADPH 氧化酶（NOX）的胞质亚基 p47(phox)，并显著抑制了 4-HNE 诱导的 NOX 激活。NOX 抑制剂 apocynin 复制了山柰酚的抗凋亡作用，表明 NOX 是其作用的重要酶。我们的研究结果表明，山柰酚通过结合 NOX 的 p47(phox)来减轻 4-HNE 诱导的 JNK 激活和凋亡，并强烈抑制神经元样细胞中 NOX-JNK 信号通路的激活。总的来说，这些结果表明，山柰酚可能是一种有效的预防 NOX 介导的神经退行性变的药物。
