Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 10 S. Pine St., Baltimore, MD 21201, USA.
J Pharmacol Exp Ther. 2011 Jun;337(3):572-82. doi: 10.1124/jpet.110.177386. Epub 2011 Jan 26.
In the mouse hippocampus normal levels of kynurenic acid (KYNA), a neuroactive metabolite synthesized in astrocytes primarily by kynurenine aminotransferase II (KAT II)-catalyzed transamination of L-kynurenine, maintain a degree of tonic inhibition of α7 nicotinic acetylcholine receptors (nAChRs). The present in vitro study was designed to test the hypothesis that α7 nAChR activity decreases when endogenous production of KYNA increases. Incubation (2-7 h) of rat hippocampal slices with kynurenine (200 μM) resulted in continuous de novo synthesis of KYNA. Kynurenine conversion to KYNA was significantly decreased by the KAT II inhibitor (S)-(-)-9-(4-aminopiperazine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3,5,6-tetrahydro-4H-1-oxa-3a-azaphenalene-5carboxylic acid (BFF122) (100 μM) and was more effective in slices from postweaned than preweaned rats. Incubation of slices from postweaned rats with kynurenine inhibited α7 nAChRs and extrasynaptic N-methyl-D-aspartate receptors (NMDARs) on CA1 stratum radiatum interneurons. These effects were attenuated by BFF122 and mimicked by exogenously applied KYNA (200 μM). Exposure of human cerebral cortical slices to kynurenine also inhibited α7 nAChRs. The α7 nAChR sensitivity to KYNA is age-dependent, because neither endogenously produced nor exogenously applied KYNA inhibited α7 nAChRs in slices from preweaned rats. In these slices, kynurenine-derived KYNA also failed to inhibit extrasynaptic NMDARs, which could, however, be inhibited by exogenously applied KYNA. In slices from preweaned and postweaned rats, glutamatergic synaptic currents were not affected by endogenously produced KYNA, but were inhibited by exogenously applied KYNA. These results suggest that in the mature brain α7 nAChRs and extrasynaptic NMDARs are in close apposition to KYNA release sites and, thereby, readily accessible to inhibition by endogenously produced KYNA.
在小鼠海马体中，正常水平的犬尿氨酸（KYNA），一种由色氨酸氨基转移酶 II（KAT II）催化 L-犬尿氨酸转氨反应合成的神经活性代谢物，对α7 烟碱型乙酰胆碱受体（nAChRs）保持一定程度的紧张性抑制。本体外研究旨在验证以下假设：当内源性 KYNA 产生增加时，α7 nAChR 活性降低。用犬尿氨酸（200μM）孵育大鼠海马切片 2-7 小时，导致 KYNA 的从头连续合成。用 KAT II 抑制剂（S）-（-）-9-（4-氨基哌嗪-1-基）-8-氟-3-甲基-6-氧代-2,3,5,6-四氢-4H-1-氧杂-3a-氮杂苯并菲-5-羧酸（BFF122）（100μM）可显著降低犬尿氨酸转化为 KYNA 的速度，且在断奶后而非断奶前大鼠的切片中效果更明显。用犬尿氨酸孵育断奶后大鼠的切片，抑制 CA1 辐射层中间神经元上的α7 nAChRs 和 extrasynaptic N-甲基-D-天冬氨酸受体（NMDARs）。这些作用可被 BFF122 减弱，并可被外源性 KYNA（200μM）模拟。将犬尿氨酸暴露于人脑皮质切片中也抑制了α7 nAChR。α7 nAChR 对 KYNA 的敏感性随年龄而变化，因为在断奶前大鼠的切片中，内源性产生的或外源性应用的 KYNA 均不能抑制α7 nAChR。在这些切片中，犬尿氨酸衍生的 KYNA 也不能抑制 extrasynaptic NMDARs，但可以被外源性应用的 KYNA 抑制。在断奶前和断奶后大鼠的切片中，内源性产生的 KYNA 不影响谷氨酸能突触电流，但可被外源性应用的 KYNA 抑制。这些结果表明，在成熟大脑中，α7 nAChR 和 extrasynaptic NMDARs 与 KYNA 释放位点紧密相邻，因此很容易被内源性产生的 KYNA 抑制。
