Effects of γ-Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and γ-Aminobutyric acid metabolism in the anesthetized rat In vivo.
Effects of γ-Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and γ-Aminobutyric acid metabolism in the anesthetized rat In vivo.
复制标题
tiagabine 抑制γ-氨基丁酸转运蛋白1 对麻醉大鼠体内脑谷氨酸和γ-氨基丁酸代谢的影响。
DOI：
10.1002/jnr.23548
复制
发表时间：
2015
影响因子：
4.2
通讯作者：
Behar,KevinL
中科院分区：
文献类型：
--
作者：
Patel,AnantB;deGraaf,RobinA;Rothman,DouglasL;Behar,KevinL
γ-氨基丁酸（GABA）从神经元释放后从细胞外间隙清除，涉及通过 GABA 转运蛋白（GAT）重新摄取到末梢和星形胶质细胞中。神经元释放 GABA 通过这两条途径的相对流量仍不清楚。本研究确定了噻加宾（神经元 GAT-1 的选择性抑制剂）对谷氨酸 (Glu) 和 GABA 代谢以及通过 GABA-谷氨酰胺 (Gln) 循环的 GABA 再合成速率的影响。氟烷麻醉的大鼠给予噻加宾（30 mg/kg，腹腔注射），45 分钟后静脉输注[1,6-13C2]葡萄糖（体内）或[2-13C]乙酸（离体）。未治疗的大鼠作为对照。使用 1 H-[ 13 C]-核磁共振波谱测量代谢物和 13 C 富集，并参考在原位冷冻大脑提取物中测量的相应终点值。通过将代谢模型与[1,6-13C2]葡萄糖输注期间体内测量的13C周转数据拟合来确定GABA能和谷氨酸能神经元的代谢通量估计。噻加宾治疗的大鼠与对照组的组织氨基酸水平和[2-13C]乙酸中的 13C 富集没有区别（P>0.05）。噻加宾降低了两个谷氨酸能神经元中葡萄糖氧化和神经递质循环的平均速率（↓18%，CMRglc(ox)Glu：对照，0.27 ± 0.05 vs. 噻加滨，0.22 ± 0.04 µmol/g/min；↓11%，Vcyc(Glu–Gln)：对照0.23 ± 0.05 对比噻加宾 0.21 ± 0.04 µmol/g/min) 和 GABA 能神经元 (↓18–25%, CMRglc(ox)GABA：对照 0.09 ± 0.02 对比噻加宾 0.07 ± 0.03 µmol/g/min； Vcyc(GABA-Gln)：对照0.08±0.02 vs.噻加宾0.07±0.03 µmol/g/min)，但谷氨酸和GABA能通量变化不显着(P>0.10)。结果表明，噻加宾对 GABA 代谢的任何减少可能是对谷氨酸能驱动减少的间接反应，而不是直接的补偿作用。 © 2015 Wiley 期刊公司。
γ‐Aminobutyric acid (GABA) clearance from the extracellular space after release from neurons involves reuptake into terminals and astrocytes through GABA transporters (GATs). The relative flows through these two pathways for GABA released from neurons remains unclear. This study determines the effect of tiagabine, a selective inhibitor of neuronal GAT‐1, on the rates of glutamate (Glu) and GABA metabolism and GABA resynthesis via the GABA–glutamine (Gln) cycle. Halothane‐anesthetized rats were administered tiagabine (30 mg/kg, i.p.) and 45 min later received an intravenous infusion of either [1,6‐13C2]glucose (in vivo) or [2‐13C]acetate (ex vivo). Nontreated rats served as controls. Metabolites and13C enrichments were measured with1H‐[13C]‐nuclear magnetic resonance spectroscopy and referenced to their corresponding endpoint values measured in extracts fromin situfrozen brain. Metabolic flux estimates of GABAergic and glutamatergic neurons were determined by fitting a metabolic model to the13C turnover data measuredin vivoduring [1,6‐13C2]glucose infusion. Tiagabine‐treated rats were indistinguishable (P> 0.05) from controls in tissue amino acid levels and in13C enrichments from [2‐13C]acetate. Tiagabine reduced average rates of glucose oxidation and neurotransmitter cycling in both glutamatergic neurons (↓18%, CMRglc(ox)Glu: control, 0.27 ± 0.05 vs. tiagabine, 0.22 ± 0.04 µmol/g/min; ↓11%, Vcyc(Glu–Gln): control 0.23 ± 0.05 vs. tiagabine 0.21 ± 0.04 µmol/g/min) and GABAergic neurons (↓18–25%, CMRglc(ox)GABA: control 0.09 ± 0.02 vs. tiagabine 0.07 ± 0.03 µmol/g/min; Vcyc(GABA–Gln): control 0.08 ± 0.02 vs. tiagabine 0.07 ± 0.03 µmol/g/min), but the changes in glutamatergic and GABAergic fluxes were not significant (P> 0.10). The results suggest that any reduction in GABA metabolism by tiagabine might be an indirect response to reduced glutamatergic drive rather than direct compensatory effects. © 2015 Wiley Periodicals, Inc.