Quinolinic Acid In Vivo Synthesis Rates, Extracellular Concentrations, and Intercompartmental Distributions in Normal and Immune‐Activated Brain as Determined by Multiple‐Isotope Microdialysis
Quinolinic Acid In Vivo Synthesis Rates, Extracellular Concentrations, and Intercompartmental Distributions in Normal and Immune‐Activated Brain as Determined by Multiple‐Isotope Microdialysis
复制标题
通过多同位素微透析测定正常和免疫激活脑中喹啉酸的体内合成率、细胞外浓度和室间分布
作者：
Karen E. Beagles;P. Morrison;M. Heyes
摘要：喹啉酸 (QUIN) 通过激活通过细胞外液 (ECF) 访问的 NMDA 受体来杀死神经元。采用体内微透析来量化 ECF QUIN 水平的动态。 [13C7]QUIN 通过探针灌注进行体内校准，以准确定量 ECF QUIN 浓度。渗透泵皮下注入 [2H3]QUIN，以量化血液对 ECF 和组织水平的贡献。根据 [13C7]QUIN 的提取分数、探针几何形状、组织扩散系数、细胞外体积分数以及血液和透析液中的 [2H3]QUIN/QUIN 比率计算局部 QUIN 生成速率以及穿过血脑屏障的流入和流出速率。在正常大脑中，85% 的 ECF QUIN 水平 (110 nM) 来自血液，而 59% 的组织匀浆 QUIN (130 pmol/g) 来自局部从头合成。在全身免疫激活（腹腔注射内毒素）过程中，血液中的QUIN水平升高（10.2倍），并导致匀浆（10.8倍）和ECF（18.5倍）的QUIN水平升高，并且来自血液的QUIN比例增加。在中枢神经系统炎症（局部输注内毒素）期间，由于局部合成率增加（146倍）和流出/流入比率减少（53%），脑匀浆（246倍）和ECF（66倍）QUIN水平增加。这些结果表明，脑匀浆测量值反映了 ECF 浓度，尽管获得的值存在定量差异。当局部脑合成大幅增加或血液 QUIN 浓度大幅升高时，将 ECF QUIN 水平维持在较低值的机制就无法做到这一点。
Abstract: Quinolinic acid (QUIN) kills neurons by activation of NMDA receptors that are accessed via the extracellular fluid (ECF). In vivo microdialysis was employed to quantify the dynamics of ECF QUIN levels. [13C7]QUIN was perfused through the probe for in vivo calibration to accurately quantify ECF QUIN concentrations. Osmotic pumps infused [2H3]QUIN subcutaneously to quantify blood contributions to ECF and tissue levels. Local QUIN production rates and influx and efflux rates across the blood‐brain barrier were calculated from the extraction fraction of [13C7]QUIN, probe geometry, tissue diffusion coefficients, the extracellular volume fraction, and [2H3]QUIN/QUIN ratios in blood and dialysates. In normal brain, 85% of ECF QUIN levels (110 nM) originated from blood, whereas 59% of tissue homogenate QUIN (130 pmol/g) originated from local de novo synthesis. During systemic immune activation (intraperitoneal injection of endotoxin), blood QUIN levels increased (10.2‐fold) and caused a rise in homogenate (10.8‐fold) and ECF (18.5‐fold) QUIN levels with an increase in the proportions of QUIN derived from blood. During CNS inflammation (local infusion of endotoxin), increases in brain homogenate (246‐fold) and ECF (66‐fold) QUIN levels occurred because of an increase in local synthesis rate (146‐fold) and a reduction in efflux/influx ratio (by 53%). These results demonstrate that brain homogenate measures are a reflection of ECF concentrations, although there are quantitative differences in the values obtained. The mechanisms that maintain ECF QUIN levels at low values cannot do so when there are large increases in local brain synthesis or when there are large elevations in blood QUIN concentrations.
严重胰岛素引起的低血糖后，大鼠新纹状体中喹啉酸的细胞外水平中度升高。
DOI：
10.1111/j.1748-1716.1990.tb08865.x
发表时间：
1990
期刊：
Acta physiologica Scandinavica
影响因子：
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作者：
Westerberg,E;Magnusson,K;Wieloch,T;Ungerstedt,U;Speciale,C;Schwarcz,R
通讯作者：
Schwarcz,R