Increased kynurenic acid levels and decreased brain kynurenine aminotransferase I in patients with down syndrome
Increased kynurenic acid levels and decreased brain kynurenine aminotransferase I in patients with down syndrome
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DOI：
10.1016/0024-3205(96)00173-7
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发表时间：
1996-04-19
期刊：
影响因子：
6.1
通讯作者：
Lubec, G
中科院分区：
文献类型：
--
作者：
Baran, H;Cairns, N;Lubec, G
兴奋性氨基酸（EAA）受体是脑生理学的中心，在学习和记忆过程中发挥重要作用。犬尿烯酸（KYNA）是色氨酸在脑中的代谢产物，可阻断所有三种经典的离子型EAA受体，也可作为N-甲基-D-天冬氨酸受体（NMDA）复合物相关甘氨酸位点的拮抗剂。我们测量了老年唐氏综合征（DS）患者（年龄46-69岁）额叶和颞叶皮质中KYNA的内源性水平以及KYNA合成酶犬尿氨酸氨基转移酶I（KAT I）和犬尿氨酸氨基转移酶II（KAT II）的活性。与对照样本（0.21+/-0.06 pmol/mg组织）相比，KYNA含量的测量结果显示DS患者额叶皮层显著增加3倍（0.67+/-0.13 pmol/mg组织; p小于或等于0.01）。在颞叶皮层中，KYNA水平增加了对照（0.41+/-0.09pmol/mg组织）的151%（p小于或等于0.05）。使用粗无细胞匀浆，在1 mM 2-含氧酸作为共底物的存在下，在KAT I的最适pH为10.0和KAT II的最适pH为7.4下测定KAT的活性。在1 mM丙酮酸存在下，额叶皮层和颞叶皮层中KAT I的KAT活性分别为2.79+/-0.52和4.55+/-1.98 pmol/mg蛋白/h，KAT II的KAT活性分别为0.98+/-0.07和1.09+/-0.14 pmol/mg蛋白/h。与对照组的脑样本相比，DS患者的额叶皮质（9.8+/-2.4%; p小于或等于0.01）和颞叶皮质（25.8+/-6.4%）中KAT I的活性降低，而KAT II水平在正常范围内。额叶皮质中神经元胆碱能标志物胆碱乙酰转移酶（ChAT）的测量显示DS显著降低（对照组的36.6+/-4.3%; p ≤ 0.01）。我们的数据表明KYNA代谢参与DS患者认知功能改变的细胞机制。虽然KAT I和KAT II的定位没有说明，但KAT I的减少可能表明神经元和/或非神经元隔室中KYNA代谢受损。
Excitatory amino acid (EAA) receptors are central to brain physiology and play important roles in learning and memory processes. Kynurenic acid (KYNA), a metabolite of tryptophan in the brain blocks all three classical ionotropic EAA receptors and also serves as an antagonist at the glycine site associated with the N-methyl-D-aspartate receptor (NMDA) complex. We measured the endogenous levels of KYNA and activities of KYNA synthesizing enzymes kynurenine aminotransferase I (KAT I) and kynurenine aminotransferase II (KAT II) in the frontal and temporal cortex of elderly Down syndrome (DS) patients (aged 46-69 years). Compared with control specimens (0.21+/-0.06 pmol/mg tissue), the measurement of KYNA content revealed a significant 3-fold increase in frontal cortex of DS patients (0.67+/-0.13 pmol/mg tissue; p less than or equal to 0.01). In temporal cortex KYNA levels were increased by 151% (p less than or equal to 0.05) of control (0.41+/-0.09 pmol/mg tissue) Using crude cell free homogenate KAT's activities were determined in the presence of the 1 mM 2-oxoacid as a co-substrate at their pH optima of 10.0 for KAT I and 7.4 for KAT II. KATs activities in the presence of 1 mM pyruvate were 2.79+/-0.52 and 4.55+/-1.98 pmol/mg protein/h for KAT I and 0.98+/-0.07 and 1.09+/-0.14 pmol/mg protein/h for KAT II in frontal cortex and temporal cortex, respectively. When compared with the brain samples of controls the activity of KAT I was reduced in frontal cortex (9.8+/-2.4%; p less than or equal to 0.01) and temporal cortex (25.8+/-6.4%) of DS patients, while KAT II levels were within the normal range. Measurement of the neuronal, cholinergic marker choline acetyltransferase (ChAT) in the frontal cortex, revealed a significant reduction (36.6+/-4.3% of control; p less than or equal to 0.01) in DS. Our data demonstrate the involvement of KYNA-metabolism in the cellular mechanisms underlying altered cognitive function in patients with DS. Although the localisation of both, KAT I and KAT II is not stated yet the reduction of KAT I may suggest impairment of KYNA metabolism in neuronal and/or nonneuronal compartments.