Murakami Yukihisa, Zhao Qi, Harada Kousuke, Tohda Michihisa, Watanabe Hiroshi, Matsumoto Kinzo
Division of Medicinal Pharmacology, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Japan.
Pharmacol Biochem Behav. 2005 Jul;81(3):616-25. doi: 10.1016/j.pbb.2005.05.004.
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.
最近一项双盲安慰剂对照研究表明，日本传统医药汉方制剂柴胡汤对血管性痴呆患者的认知障碍具有有益作用。然而，该方剂治疗作用的神经元机制仍有待阐明。我们使用慢性脑灌注不足模型，研究柴胡汤对小鼠认知功能障碍的影响，以阐明其作用机制。通过永久性结扎双侧颈总动脉（2VO）诱导慢性脑灌注不足。柴胡汤及其主要成分钩藤可改善2VO诱导的学习缺陷，而不含钩藤的柴胡汤则无此作用。柴胡汤和钩藤的作用被选择性毒蕈碱M1拮抗剂哌仑西平阻断。在管优势试验中，2VO诱导小鼠的主动行为发生率增加。与给予赋形剂的对照组相比，给予柴胡汤的2VO小鼠的主动行为发生率显著降低，而不含钩藤的柴胡汤和钩藤对2VO诱导的主动行为几乎没有影响。2VO导致脑内乙酰胆碱（ACh）含量显著降低，每日给予柴胡汤或钩藤可使ACh水平升高至假手术对照组的水平。这些结果表明，柴胡汤对慢性灌注不足引起的空间记忆缺陷具有改善作用，且该作用主要归因于钩藤。此外，提示柴胡汤和钩藤的作用至少部分是通过刺激毒蕈碱M1受体介导的。
