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.
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.
复制标题
DOI：
10.1016/j.jpba.2014.11.019
复制
发表时间：
2015-02
影响因子：
3.4
通讯作者：
Yimin Niu;Feng Li;Chikako Inada;Ken Tanaka;Shiro Watanabe;H. Fujiwara;S. Sasaki‐Hamada;J. Oka;Kinzo Matsumoto
中科院分区：
文献类型：
--
作者：
Yimin Niu;Feng Li;Chikako Inada;Ken Tanaka;Shiro Watanabe;H. Fujiwara;S. Sasaki‐Hamada;J. Oka;Kinzo Matsumoto
在我们以前的研究中，每日服用由钩藤和其他10种不同的生药组成的汉方制剂chotosan（CTS），以类似于乙酰胆碱酯酶抑制剂tacrine的方式改善了包括2型糖尿病db/db小鼠在内的几种痴呆动物模型的认知缺陷。本研究探讨了代谢组学的CTS indb/db小鼠，2型糖尿病模型，和m/mmice，非糖尿病对照品系，以确定外源性和内源性化学物质的管理CTS使用高效液相色谱仪配备了轨道阱混合傅立叶变换质谱仪。结果表明，CTS全身给药20天后，钩藤碱、毛藤碱和corynoxeine等Uncalia植物衍生生物碱在db/dbandm/m小鼠的血浆和脑中分布，并诱导了四种主要代谢途径的改变，即，(1)嘌呤，（2）色氨酸，（3）半胱氨酸和蛋氨酸，（4）甘油磷脂。此外，CTS处理的db/db小鼠血浆和脑中的甘油磷酸胆碱（GPC）水平显著高于溶剂处理的对照动物。用器官型海马脑片培养的体外实验结果表明，GPC（10-30 μM）和他克林以一种与毒蕈碱受体拮抗剂东莨菪碱可逆的方式保护海马细胞免受N-甲基-d-天冬氨酸诱导的兴奋性毒性，而GPC在体外对乙酰胆碱酯酶的活性没有影响。结果表明，CTS全身给药后，一些具有神经药理活性的CTS成分分布在血浆和脑组织中，并可能随后影响某些代谢途径，包括甘油磷脂代谢和认知功能indb/db小鼠。此外，目前的代谢组学分析表明，GPC是一个假定的内源性化学物质，可能参与了他克林样行动的CTS在本糖尿病动物模型。
In our previous study, the daily administration of chotosan (CTS), a Kampo formula consisting ofUncariaand other 10 different crude drugs, ameliorated cognitive deficits in several animal models of dementia including type 2 diabeticdb/dbmice in a similar manner to tacrine, an acetylcholinesterase inhibitor. The present study investigated the metabonomics of CTS indb/dbmice, a type 2 diabetes model, andm/mmice, 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 ofUncaliaplant-derived alkaloids such as rhynchophylline, hirsuteine, and corynoxeine in the plasma and brains ofdb/dbandm/mmice and induced alterations in four major metabolic pathways;i.e., (1) purine, (2) tryptophan, (3) cysteine and methionine, (4) glycerophospholipids indb/dbmice. Moreover, glycerophosphocholine (GPC) levels in the plasma and brain were significantly higher in CTS-treateddb/dbmice than in vehicle-treated control animals. The results of thein vitroexperiment 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 acetylcholinesterasein 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 indb/dbmice. 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.