Du F, Williamson J, Bertram E, Lothman E, Okuno E, Schwarcz R
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228.
Neuroscience. 1993 Aug;55(4):975-89. doi: 10.1016/0306-4522(93)90312-4.
The kynurenine pathway metabolites quinolinic acid and kynurenic acid have been hypothetically linked to the occurrence of seizure phenomena. The present immunohistochemical study reports the activation of astrocytes containing three enzymes responsible for the metabolism of quinolinic acid and kynurenic acid in a rat model of chronic epilepsy. Rats received 90 min of patterned electrical stimulation through a bipolar electrode stereotaxically positioned in one hippocampus. This treatment induces non-convulsive limbic status epilepticus that leads to chronic, spontaneous, recurrent seizures. One month after the status epilepticus, the rats showed neuronal loss and gliosis in the piriform cortex, thalamus, and hippocampus, particularly on the side contralateral to the stimulation. Astrocytes containing the kynurenic acid biosynthetic enzyme (kynurenine aminotransferase) and the enzymes for the biosynthesis and degradation of quinolinic acid (3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase, respectively) became highly hypertrophied in brain areas where neurodegeneration occurred. Detailed qualitative and quantitative analyses were performed in the hippocampus. In CA1 and CA3 regions, the immunostained surface area of reactive astrocytes increased up to five-fold as compared to controls. Enlarged cells containing the three enzymes were mainly observed in the stratum radiatum, whereas the stratum pyramidale, in which neuronal somata degenerated, showed relatively fewer reactive glial cells. Hypertrophied kynurenine aminotransferase- and 3-hydroxyanthranilic acid oxygenase-immunoreactive cells were comparable in their morphology and distribution pattern. In contrast, reactive quinolinic acid phosphoribosyl transferase-positive glial cells displayed diversified sizes and shapes. Some very large quinolinic acid phosphoribosyl transferase-immunoreactive cells were noticed in the molecular layer of the dentate gyrus. In the hippocampus, the number of immunoreactive glial cells increased in parallel to the hypertrophic responses. In addition, pronounced increases in immunoreactivities, associated with hypertrophied astrocytes, occurred around lesioned sites in the thalamus and piriform cortex. These findings indicate that kynurenine metabolites derived from glial cells may play a role in chronic epileptogenesis.
犬尿氨酸途径代谢产物喹啉酸和犬尿喹啉酸被推测与癫痫发作现象的发生有关。本免疫组织化学研究报告了在慢性癫痫大鼠模型中，含有负责喹啉酸和犬尿喹啉酸代谢的三种酶的星形胶质细胞的激活情况。大鼠通过立体定位在一侧海马体中的双极电极接受90分钟的模式电刺激。这种治疗诱发非惊厥性边缘性癫痫持续状态，进而导致慢性、自发性、复发性癫痫发作。癫痫持续状态一个月后，大鼠在梨状皮质、丘脑和海马体中出现神经元丢失和胶质细胞增生，尤其是在刺激对侧。含有犬尿喹啉酸生物合成酶（犬尿氨酸转氨酶）以及喹啉酸生物合成和降解酶（分别为3-羟基邻氨基苯甲酸加氧酶和喹啉酸磷酸核糖基转移酶）的星形胶质细胞在发生神经变性的脑区中高度肥大。在海马体中进行了详细的定性和定量分析。在CA1和CA3区域，与对照组相比，反应性星形胶质细胞的免疫染色表面积增加了五倍。含有这三种酶的增大细胞主要在辐射层中观察到，而神经元胞体发生退化的锥体层中反应性胶质细胞相对较少。肥大的犬尿氨酸转氨酶和3-羟基邻氨基苯甲酸加氧酶免疫反应性细胞在形态和分布模式上具有可比性。相比之下，反应性喹啉酸磷酸核糖基转移酶阳性胶质细胞呈现出多样化的大小和形状。在齿状回分子层中发现了一些非常大的喹啉酸磷酸核糖基转移酶免疫反应性细胞。在海马体中，免疫反应性胶质细胞的数量与肥大反应平行增加。此外，在丘脑和梨状皮质的损伤部位周围，与肥大星形胶质细胞相关的免疫反应性明显增加。这些发现表明，源自胶质细胞的犬尿氨酸代谢产物可能在慢性癫痫发生中起作用。
