Yokukansan inhibits neuronal death during ER stress by regulating the unfolded protein response.
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.
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.
Toru
T
Hiratsuka
Shinsuke
S
Matsuzaki
Shingo
S
Miyata
Mitsuhiro
M
Kinoshita
Kazuaki
K
Kakehi
Shinji
S
Nishida
Taiichi
T
Katayama
Masaya
M
Tohyama
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000187:drug effects*; D011489:Protein Denaturation; D015398:Signal Transduction
D004365:Drugs, Chinese Herbal; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; C524644:Yi-Gan San