Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.
PLoS One. 2010 Oct 12;5(10):e13280. doi: 10.1371/journal.pone.0013280.
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.
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.
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.
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.
最近，有几项研究报告称，日本传统药物和汉方制剂（Tsumura TJ-54） Yokukansan 可能成为治疗阿尔茨海默病（AD）的新药。内质网（ER）应激被认为在 AD 的发病机制中起着重要作用，特别是在神经元死亡中。因此，我们研究了 Yokukansan 对 ER 应激诱导的神经毒性以及与家族性 AD 相关的早老素-1 突变相关细胞死亡的影响。
我们采用 WST-1 检测法和形态学变化监测来评估 Yokukansan 处理或其成分处理后细胞活力。Western blot 和 PCR 用于观察 GRP78/BiP、caspase-4 和 C/EBP 同源蛋白的表达水平。
Yokukansan 抑制 ER 应激期间的神经元死亡，其中 Yokukansan 的一种成分——蛇床子具有特别显著的效果。我们还表明，Yokukansan 和蛇床子影响 ER 应激后的未折叠蛋白反应，这些药物抑制 caspase-4 的激活，从而抑制 ER 应激诱导的神经元死亡。此外，我们发现 Yokukansan 和蛇床子对 ER 应激的保护作用可能归因于这两种药物中的阿魏酸含量。
我们的结果表明，Yokukansan、蛇床子和阿魏酸可预防 ER 应激诱导的神经元细胞死亡，可能为 AD 提供一种新的潜在治疗方法。
