title: Chemical profiling with HPLC-FTMS of exogenous and endogenous chemicals susceptible to the administration of chotosan in an animal model of type 2 diabetes-induced dementia.
abstract: In our previous study, the daily administration of chotosan (CTS), a Kampo formula consisting of Uncaria and other 10 different crude drugs, ameliorated cognitive deficits in several animal models of dementia including type 2 diabetic db/db mice in a similar manner to tacrine, an acetylcholinesterase inhibitor. The present study investigated the metabonomics of CTS in db/db mice, a type 2 diabetes model, and m/m mice, a non-diabetes control strain, to identify the exogenous and endogenous chemicals susceptible to the administration of CTS using high performance liquid chromatography equipped with an orbitrap hybrid Fourier transform mass spectrometer. The results obtained revealed that the systemic administration of CTS for 20 days led to the distribution of Uncalia plant-derived alkaloids such as rhynchophylline, hirsuteine, and corynoxeine in the plasma and brains of db/db and m/m mice and induced alterations in four major metabolic pathways; i.e., (1) purine, (2) tryptophan, (3) cysteine and methionine, (4) glycerophospholipids in db/db mice. Moreover, glycerophosphocholine (GPC) levels in the plasma and brain were significantly higher in CTS-treated db/db mice than in vehicle-treated control animals. The results of the in vitro experiment using organotypic hippocampal slice cultures demonstrated that GPC (10-30 μM), as well as tacrine, protected hippocampal cells from N-methyl-d-aspartate-induced excitotoxicity in a manner that was reversible with the muscarinic receptor antagonist scopolamine, whereas GPC had no effect on the activity of acetylcholinesterase in vitro. Our results demonstrated that some CTS constituents with neuropharmacological activity were distributed in the plasma and brain tissue following the systemic administration of CTS and may subsequently have affected some metabolic pathways including glycerophospholipid metabolism and cognitive function in db/db mice. Moreover, the present metabonomic analysis suggested that GPC is a putative endogenous chemical that may be involved in the tacrine-like actions of CTS in the present diabetic animal model.
authors.affiliation: Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Inada
authors.affiliation: Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Sasaki-Hamada
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Oka
authors.affiliation: Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: mkinzo@inm.u-toyama.ac.jp.
authors.forename: Kinzo
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003704:Dementia / Q000209:etiology* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008817:Mice, Mutant Strains; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D004365:Drugs, Chinese Herbal; D018696:Neuroprotective Agents; C120250:choto-san
keywords: Chotosan; Glycerophosphocholine; HPLC-FTMS; Metabonomics; Type 2 diabetic model