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Chotosan ameliorates cognitive and emotional deficits in an animal model of type 2 diabetes: possible involvement of cholinergic and VEGF/PDGF mechanisms in the brain

Qi Zhao1, Yimin Niu1, Kinzo Matsumoto1*, Koichi Tsuneyama2, Ken Tanaka3, Takeshi Miyata45 and Takako Yokozawa6

Author Affiliations

1 Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, 2630 Sugitani, Toyama 930-0194, Japan

2 Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

3 Division of Pharmacognosy, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

4 Division of Biomedical Informatics, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

5 Laboratory of Presymptomatic Medical Pharmacology, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto, 860-0082, Japan

6 Collaboration Division, Organization for Promotion of Regional Collaboration, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan

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BMC Complementary and Alternative Medicine 2012, 12:188  doi:10.1186/1472-6882-12-188

Published: 20 October 2012



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.

Chotosan; Diabetes; Cognitive deficits; Cholinergic system; VEGF/PDGF systems