Yokukansan Inhibits Neuronal Death during ER Stress by Regulating the Unfolded Protein Response
Yokukansan Inhibits Neuronal Death during ER Stress by Regulating the Unfolded Protein Response
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DOI：
10.1371/journal.pone.0013280
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发表时间：
2010-10-12
期刊：
影响因子：
3.7
通讯作者：
Tohyama, Masaya
中科院分区：
文献类型：
--
作者：
Hiratsuka, Toru;Matsuzaki, Shinsuke;Tohyama, Masaya
背景：近年来，一些研究报道了日本传统药物Yokukansan （Tsumura TJ-54）作为治疗阿尔茨海默病（AD）的潜在新药。内质网应激在阿尔茨海默病的发病机制中起重要作用，特别是在神经元死亡中。因此，我们研究了Yokukansan对内质网应激诱导的神经毒性和家族性ad相关的早老素-1突变相关细胞死亡的影响。方法：我们采用WST-1检测和监测形态变化来评估Yokukansan或其成分处理后的细胞活力。采用Western blotting和PCR检测GRP78/BiP、caspase-4和C/EBP同源蛋白的表达水平。结果：横坎散抑制内质网应激下的神经元死亡，其中尤以横坎散成分蛇床子根（Senkyu）有效。我们还发现Yokukansan和Senkyu影响内质网应激后未折叠蛋白的反应，这些药物抑制caspase-4的激活，从而抑制内质网应激诱导的神经元死亡。此外，我们发现横山和仙球对内质网应激的保护作用可能归因于这两种药物的阿魏酸含量。结论：我们的研究结果表明，横山、仙球和阿魏酸对内质网应激诱导的神经元细胞死亡具有保护作用，可能为阿尔茨海默病提供新的治疗方法。
Background: Recently, several studies have reported Yokukansan (Tsumura TJ-54), a traditional Japanese medicine, as a potential new drug for the treatment of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress is known to play an important role in the pathogenesis of AD, particularly in neuronal death. Therefore, we examined the effect of Yokukansan on ER stress-induced neurotoxicity and on familial AD-linked presenilin-1 mutation-associated cell death.Methods: We employed the WST-1 assay and monitored morphological changes to evaluate cell viability following Yokukansan treatment or treatment with its components. Western blotting and PCR were used to observe the expression levels of GRP78/BiP, caspase-4 and C/EBP homologous protein.Results: Yokukansan inhibited neuronal death during ER stress, with Cnidii Rhizoma (Senkyu), a component of Yokukansan, being particularly effective. We also showed that Yokukansan and Senkyu affect the unfolded protein response following ER stress and that these drugs inhibit the activation of caspase-4, resulting in the inhibition of ER stress-induced neuronal death. Furthermore, we found that the protective effect of Yokukansan and Senkyu against ER stress could be attributed to the ferulic acid content of these two drugs.Conclusions: Our results indicate that Yokukansan, Senkyu and ferulic acid are protective against ER stress-induced neuronal cell death and may provide a possible new treatment for AD.