Durairajan Siva Sundara Kumar, Huang Ying-Yu, Yuen Pui-Yee, Chen Lei-Lei, Kwok Ka-Yan, Liu Liang-Feng, Song Ju-Xian, Han Quan-Bin, Xue Lei, Chung Sookja K, Huang Jian-Dong, Baum Larry, Senapati Sanjib, Li Min
Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Natural Products Chemistry & Analysis Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
PLoS One. 2014 Mar 26;9(3):e92954. doi: 10.1371/journal.pone.0092954. eCollection 2014.
Huanglian-Jie-Du-Tang (HLJDT) is a famous traditional Chinese herbal formula that has been widely used clinically to treat cerebral ischemia. Recently, we found that berberine, a major alkaloid compound in HLJDT, reduced amyloid-β (Aβ) accumulation in an Alzheimer's disease (AD) mouse model. In this study, we compared the effects of HLJDT, four single component herbs of HLJDT (Rhizoma coptidis (RC), Radix scutellariae (RS), Cortex phellodendri (CP) and Fructus gardenia (FG)) and the modified formula of HLJDT (HLJDT-M, which is free of RS) on the regulatory processing of amyloid-β precursor protein (APP) in an in vitro model of AD. Here we show that treatment with HLJDT-M and its components RC, CP, and the main compound berberine on N2a mouse neuroblastoma cells stably expressing human APP with the Swedish mutation (N2a-SwedAPP) significantly decreased the levels of full-length APP, phosphorylated APP at threonine 668, C-terminal fragments of APP, soluble APP (sAPP)-α and sAPPβ-Swedish and reduced the generation of Aβ peptide in the cell lysates of N2a-SwedAPP. HLJDT-M showed more significant APP- and Aβ- reducing effects than berberine, RC or CP treatment alone. In contrast, HLJDT, its component RS and the main active compound of RS, baicalein, strongly increased the levels of all the metabolic products of APP in the cell lysates. The extract from FG, however, did not influence APP modulation. Interestingly, regular treatment of TgCRND8 APP transgenic mice with baicalein exacerbated the amyloid plaque burden, APP metabolism and Aβ production. Taken together, these data provide convincing evidence that HLJDT and baicalein treatment can increase the amyloidogenic metabolism of APP which is at least partly responsible for the baicalein-mediated Aβ plaque increase in the brains of TgCRND8 mice. On the other hand, HLJDT-M significantly decreased all the APP metabolic products including Aβ. Further study of HLJDT-M for therapeutic use in treating AD is warranted.
黄连解毒汤（HLJDT）是一种著名的传统中药方剂，在临床上已被广泛用于治疗脑缺血。最近，我们发现黄连解毒汤中的主要生物碱化合物小檗碱可减少阿尔茨海默病（AD）小鼠模型中的淀粉样β蛋白（Aβ）积累。在本研究中，我们比较了黄连解毒汤、黄连解毒汤的四种单味药（黄连（RC）、黄芩（RS）、黄柏（CP）和栀子（FG））以及改良的黄连解毒汤（HLJDT-M，不含RS）对AD体外模型中淀粉样β前体蛋白（APP）调节加工的影响。在此我们表明，用HLJDT-M及其成分RC、CP和主要化合物小檗碱处理稳定表达带有瑞典突变的人APP的N2a小鼠神经母细胞瘤细胞（N2a-SwedAPP），可显著降低全长APP、苏氨酸668位磷酸化APP、APP的C末端片段、可溶性APP（sAPP）-α和sAPPβ-瑞典的水平，并减少N2a-SwedAPP细胞裂解物中Aβ肽的产生。HLJDT-M比单独使用小檗碱、RC或CP治疗显示出更显著的降低APP和Aβ的作用。相比之下，黄连解毒汤、其成分RS以及RS的主要活性化合物黄芩苷可强烈增加细胞裂解物中APP所有代谢产物的水平。然而，栀子提取物对APP调节没有影响。有趣的是，用黄芩苷定期处理TgCRND8 APP转基因小鼠会加剧淀粉样斑块负担、APP代谢和Aβ产生。综上所述，这些数据提供了令人信服的证据，表明黄连解毒汤和黄芩苷处理可增加APP的淀粉样生成代谢，这至少部分是黄芩苷介导的TgCRND8小鼠大脑中Aβ斑块增加的原因。另一方面，HLJDT-M显著降低了包括Aβ在内的所有APP代谢产物。有必要对HLJDT-M用于治疗AD进行进一步研究。
