Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
J Ethnopharmacol. 2011 Jun 1;135(3):737-46. doi: 10.1016/j.jep.2011.04.010. Epub 2011 Apr 12.
Yokukansan (YKS) is a Japanese traditional herbal medicine and has been used for the treatment of the behavioral and psychological symptoms of dementia (BPSD). The present study aimed to clarify the effects of YKS on learning and memory impairments, and its mechanisms of action in olfactory bulbectomized (OBX) mice, one of the animal models of Alzheimer's disease (AD).
OBX or sham-operated ddY mice were treated with YKS or donepezil (DPZ), a reference drug, and their cognitive performances were tested by the modified Y-maze test, novel object recognition test, and fear conditioning test to elucidate the spatial working memory, non-spatial short-term memory, and long-term memory, respectively. After completing the behavioral experiments, the expression level of cholinergic marker proteins and the activity of acetylcholinesterase (AChE) in the brain were analyzed by western blotting and Ellman's method, respectively.
OBX caused spatial working memory and non-spatial working memory impairments that were reversed by YKS and also by DPZ; however, YKS failed to affect the long-term memory deficits. Amelioration of the spatial working memory by YKS was reversible by scopolamine, a muscarinic receptor antagonist. YKS treatment reversed OBX-induced down-regulation of choline acetyltransferase and muscarinic muscarinic M₁ receptor expression without affecting muscarinic M₃ receptor expression or AChE activity.
These results demonstrate that YKS improves short-term memory deficit caused by OBX and that the effect is at least partly mediated by muscarinic receptor stimulation and the normalization of central cholinergic systems. The present findings also suggest that YKS has a therapeutic effect not only on BPSD, but also on memory impairment of AD.
和汉三才散（YKS）是一种日本传统草药，用于治疗痴呆的行为和心理症状（BPSD）。本研究旨在阐明 YKS 对学习和记忆障碍的影响，及其在嗅球切除术（OBX）小鼠中的作用机制，OBX 小鼠是阿尔茨海默病（AD）的动物模型之一。
OBX 或假手术 ddY 小鼠用 YKS 或多奈哌齐（DPZ）治疗，一种参考药物，并通过改良 Y 迷宫测试、新物体识别测试和恐惧条件测试测试其认知表现，分别阐明空间工作记忆、非空间短期记忆和长期记忆。完成行为实验后，通过 Western blot 和 Ellman 法分析大脑中胆碱能标志物蛋白的表达水平和乙酰胆碱酯酶（AChE）的活性。
OBX 导致空间工作记忆和非空间工作记忆障碍，YKS 和 DPZ 均可逆转；然而，YKS 未能影响长期记忆缺陷。YKS 对空间工作记忆的改善可被毒蕈碱受体拮抗剂东莨菪碱逆转。YKS 治疗可逆转 OBX 诱导的胆碱乙酰转移酶和毒蕈碱 M₁受体表达下调，而不影响毒蕈碱 M₃受体表达或 AChE 活性。
这些结果表明，YKS 改善了 OBX 引起的短期记忆障碍，其作用至少部分是通过毒蕈碱受体刺激和中枢胆碱能系统的正常化介导的。本研究结果还表明，YKS 不仅对 BPSD 具有治疗作用，而且对 AD 的记忆障碍也具有治疗作用。
