Wu Hui-Qiu, Rassoulpour Arash, Goodman Jeffrey H, Scharfman Helen E, Bertram Edward H, Schwarcz Robert
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, U.S.A.
Epilepsia. 2005 Jul;46(7):1010-6. doi: 10.1111/j.1528-1167.2005.67404.x.
The tryptophan metabolite kynurenic acid (KYNA) and its synthetic derivative, 7-chlorokynurenic acid (7-Cl-KYNA), are antagonists of the glycine co-agonist ("glycine(B)") site of the N-methyl-D-aspartate (NMDA)-receptor. Both compounds have neuroprotective and anticonvulsive properties but do not readily penetrate the blood-brain barrier. However, KYNA and 7-Cl-KYNA can be formed in, and released from, astrocytes after the peripheral administration of their transportable precursors kynurenine and 4-chlorokynurenine, respectively. The present study was designed to examine these biosynthetic processes, as well as astrogliosis, in animals with spontaneously recurring seizures.
The fate and formation of KYNA and 7-Cl-KYNA was studied in vivo (microdialysis) and in vitro (tissue slices) in rats exhibiting chronic seizure activity (pilocarpine model) and in appropriate controls. Neuronal loss and gliosis in these animals were examined immunohistochemically.
In vivo microdialysis revealed higher ambient extracellular KYNA levels and enhanced de novo formation of 7-Cl-KYNA in the entorhinal cortex and hippocampus in epileptic rats. Complementary studies in tissue slices showed increased neosynthesis of KYNA and 7-Cl-KYNA in the same two brain areas. Microscopic analysis revealed pronounced astrocytic reactions in entorhinal cortex and hippocampus in epileptic animals.
These results demonstrate that the epileptic brain can synthesize glycine(B) receptor antagonists in situ. Astrogliosis probably accounts for their enhanced production in chronically epileptic rats. These results bode well for the use of 4-chlorokynurenine in the treatment of chronic seizure disorders.
色氨酸代谢产物犬尿喹啉酸（KYNA）及其合成衍生物7-氯犬尿喹啉酸（7-Cl-KYNA）是N-甲基-D-天冬氨酸（NMDA）受体甘氨酸协同激动剂（“甘氨酸（B）”）位点的拮抗剂。这两种化合物都具有神经保护和抗惊厥特性，但不易穿透血脑屏障。然而，分别在外周给予可转运前体色氨酸和4-氯色氨酸后，星形胶质细胞中可形成并释放KYNA和7-Cl-KYNA。本研究旨在检查自发性复发性癫痫动物中的这些生物合成过程以及星形胶质细胞增生。
在表现出慢性癫痫活动的大鼠（匹鲁卡品模型）及适当对照中，通过体内（微透析）和体外（组织切片）研究了KYNA和7-Cl-KYNA的去向和形成。通过免疫组织化学检查这些动物的神经元丢失和胶质细胞增生情况。
体内微透析显示，癫痫大鼠内嗅皮质和海马中的细胞外KYNA水平较高，且7-Cl-KYNA的从头合成增强。组织切片的补充研究表明，相同的两个脑区中KYNA和7-Cl-KYNA的新合成增加。显微镜分析显示，癫痫动物的内嗅皮质和海马中有明显的星形细胞反应。
这些结果表明，癫痫脑可原位合成甘氨酸（B）受体拮抗剂。星形胶质细胞增生可能是慢性癫痫大鼠中其产量增加的原因。这些结果为4-氯色氨酸用于治疗慢性癫痫疾病带来了良好的前景。
