A recent double-blind and placebo-controlled study demonstrated a beneficial effect of
Choto-san, a
Kampo (
traditional medicine of Japan) formula, on
cognitive impairment in patients with
vascular dementia. However, the neuronal mechanism underlying the
therapeutic effects of this formula remains to be clarified. Using a chronic cerebral hypoperfusion model, we investigated the effect of
Choto-san on
cognitive dysfunction in mice to clarify its mechanism of actions. Chronic cerebral hypoperfusion was induced by permanent occlusion of both the common carotid arteries (2VO).
Choto-san and Uncaria, a major constituent of
Choto-san, caused an improvement in 2VO-induced learning deficits, whereas Uncaria-free
Choto-san did not. The effects of
Choto-san and Uncaria were blocked by
pirenzepine, a selective
muscarinic M1 antagonist. In a tube-dominance test, 2VO induced increased rates of assertive behavior in mice. 2VO mice administered
Choto-san showed significantly reduced rates of assertive behavior compared to vehicle-treated controls, whereas Uncaria-free
Choto-san and Uncaria had little effect on 2VO-induced assertive behavior. 2VO caused a significant decrease in the level of
acetylcholine (ACh) contents in the brain, and the daily administration of
Choto-san or Uncaria raised the ACh level to that in the
sham-operated controls. These results suggest that
Choto-san has an ameliorating effect on the spatial memory deficit caused by chronic hypoperfusion, and that the effect is mainly attributable to Uncaria. Moreover, it was suggested that the effects of
Choto-san and Uncaria are at least partly mediated by stimulation of the
muscarinic M1 receptor.