Amino acids inhibit kynurenic acid formation via suppression of kynurenine uptake or kynurenic acid synthesis in rat brain in vitro.
Amino acids inhibit kynurenic acid formation via suppression of kynurenine uptake or kynurenic acid synthesis in rat brain in vitro.
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DOI：
10.1186/s40064-015-0826-9
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Fukuwatari T
中科院分区：
文献类型：
--
作者：
Sekine A;Okamoto M;Kanatani Y;Sano M;Shibata K;Fukuwatari T
色氨酸代谢产物犬尿烯酸（KYNA）是内源性脑浓度下α7烟碱乙酰胆碱受体的优先拮抗剂。最近的研究表明，大脑KYNA水平的增加与精神疾病如精神分裂症和抑郁症有关。产生KYNA的酶对氨基酸具有广泛的底物特异性，并且犬尿氨酸（KYN）（KYNA的直接前体）的脑摄取是通过大的中性氨基酸转运蛋白（LAT）进行的。在本研究中，为了找出具有抑制KYNA产生潜力的氨基酸，我们全面研究了蛋白原氨基酸对体外大鼠脑中KYNA形成和KYN摄取的影响。将大鼠脑的皮质切片在含有生理浓度的KYN和单个氨基酸的Krebs-Ringer缓冲液中孵育2小时。19种氨基酸中的10种（具体而言，亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸、酪氨酸、丙氨酸、半胱氨酸、谷氨酰胺、谷氨酸和天冬氨酸）在1 mmol/L时显著降低KYNA形成。这些氨基酸以剂量依赖性方式显示出抑制作用，并且在生理浓度下部分抑制KYNA的产生。亮氨酸，异亮氨酸，甲硫氨酸，苯丙氨酸和酪氨酸，所有LAT底物，也降低组织KYN浓度的剂量依赖性方式，其抑制率与KYNA形成显着相关的KYN摄取。这些结果表明，五种LAT底物通过阻断KYN转运抑制KYNA形成，而其他氨基酸通过阻断脑中的KYNA合成反应起作用。氨基酸可以是通过操纵脑中KYNA形成来调节脑功能的良好工具。这种方法可能有助于治疗和预防与KYNA水平增加相关的神经和精神疾病。
The tryptophan metabolite, kynurenic acid (KYNA), is a preferential antagonist of the α7 nicotinic acetylcholine receptor at endogenous brain concentrations. Recent studies have suggested that increase of brain KYNA levels is involved in psychiatric disorders such as schizophrenia and depression. KYNA-producing enzymes have broad substrate specificity for amino acids, and brain uptake of kynurenine (KYN), the immediate precursor of KYNA, is via large neutral amino acid transporters (LAT). In the present study, to find out amino acids with the potential to suppress KYNA production, we comprehensively investigated the effects of proteinogenic amino acids on KYNA formation and KYN uptake in rat brain in vitro. Cortical slices of rat brain were incubated for 2 h in Krebs-Ringer buffer containing a physiological concentration of KYN with individual amino acids. Ten out of 19 amino acids (specifically, leucine, isoleucine, phenylalanine, methionine, tyrosine, alanine, cysteine, glutamine, glutamate, and aspartate) significantly reduced KYNA formation at 1 mmol/L. These amino acids showed inhibitory effects in a dose-dependent manner, and partially inhibited KYNA production at physiological concentrations. Leucine, isoleucine, methionine, phenylalanine, and tyrosine, all LAT substrates, also reduced tissue KYN concentrations in a dose-dependent manner, with their inhibitory rates for KYN uptake significantly correlated with KYNA formation. These results suggest that five LAT substrates inhibit KYNA formation via blockade of KYN transport, while the other amino acids act via blockade of the KYNA synthesis reaction in brain. Amino acids can be a good tool to modulate brain function by manipulation of KYNA formation in the brain. This approach may be useful in the treatment and prevention of neurological and psychiatric diseases associated with increased KYNA levels.
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影响因子：
2.7
作者：
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