Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, 2630 Sugitani, Toyama 930-0194, Japan.
BMC Complement Altern Med. 2012 Oct 20;12:188. doi: 10.1186/1472-6882-12-188.
Diabetes is one of the risk factors for cognitive deficits such as Alzheimer's disease. To obtain a better understanding of the anti-dementia effect of chotosan (CTS), a Kampo formula, we investigated its effects on cognitive and emotional deficits of type 2 diabetic db/db mice and putative mechanism(s) underlying the effects.
Seven-week-old db/db mice received daily administration of CTS (375 - 750 mg/kg, p.o.) and the reference drug tacrine (THA: 2.5 mg/kg, i.p.) during an experimental period of 7 weeks. From the age of 9-week-old, the animals underwent the novel object recognition test, the modified Y-maze test, and the water maze test to elucidate cognitive performance and the elevated plus maze test to elucidate anxiety-related behavior. After completing behavioral studies, Western blotting and immunohistochemical studies were conducted.
Compared with age-matched non-diabetic control strain (m/m) mice, db/db mice exhibited impaired cognitive performance and an increased level of anxiety. CTS ameliorated cognitive and emotional deficits of db/db mice, whereas THA improved only cognitive performance. The phosphorylated levels of Akt and PKCα in the hippocampus were significantly lower and higher, respectively, in db/db mice than in m/m mice. Expression levels of the hippocampal cholinergic marker proteins and the number of the septal cholinergic neurons were also reduced in db/db mice compared with those in m/m mice. Moreover, the db/db mice had significantly reduced levels of vasculogenesis/angiogenesis factors, vascular endothelial growth factor (VEGF), VEGF receptor type 2, platelet-derived growth factor-B, and PDGF receptor β, in the hippocampus. CTS and THA treatment reversed these neurochemical and histological alterations caused by diabetes.
These results suggest that CTS ameliorates diabetes-induced cognitive deficits by protecting central cholinergic and VEGF/PDGF systems via Akt signaling pathway and that CTS exhibits the anxiolytic effect via neuronal mechanism(s) independent of cholinergic or VEGF/PDGF systems in db/db mice.
糖尿病是导致认知功能障碍（如阿尔茨海默病）的危险因素之一。为了更好地了解汉方药柴苓汤（CTS）的抗痴呆作用，我们研究了其对 2 型糖尿病 db/db 小鼠认知和情绪缺陷的影响及其潜在机制。
7 周龄 db/db 小鼠接受 CTS（375-750mg/kg，po）和参比药物他克林（THA：2.5mg/kg，ip）的每日给药，实验期为 7 周。从 9 周龄开始，动物进行新物体识别测试、改良 Y 迷宫测试和水迷宫测试以阐明认知表现，以及高架十字迷宫测试以阐明焦虑相关行为。完成行为研究后，进行 Western blot 和免疫组织化学研究。
与年龄匹配的非糖尿病对照品系（m/m）小鼠相比，db/db 小鼠表现出认知表现受损和焦虑水平升高。CTS 改善了 db/db 小鼠的认知和情绪缺陷，而 THA 仅改善了认知表现。与 m/m 小鼠相比，db/db 小鼠海马中磷酸化 Akt 和 PKCα 的水平分别显著降低和升高。海马胆碱能标志物蛋白的表达水平和隔区胆碱能神经元的数量也在 db/db 小鼠中减少。此外，db/db 小鼠海马中的血管生成/血管生成因子、血管内皮生长因子（VEGF）、VEGF 受体 2、血小板衍生生长因子-B 和 PDGF 受体β的水平也显著降低。CTS 和 THA 治疗逆转了糖尿病引起的这些神经化学和组织学改变。
这些结果表明，CTS 通过 Akt 信号通路保护中枢胆碱能和 VEGF/PDGF 系统改善糖尿病引起的认知缺陷，并且 CTS 通过与胆碱能或 VEGF/PDGF 系统无关的神经元机制在 db/db 小鼠中表现出抗焦虑作用。
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