与正常对照相比，原位生成的7-氯犬尿氨酸对边缘性癫痫大鼠的诱发反应有不同影响。

Zhang De Xing, Williamson John M, Wu Hu-Qui, Schwarcz Robert, Bertram Edward H

Department of Neurology, University of Virginia, Charlottesville, Virginia 22908-0394, USA.

Epilepsia. 2005 Nov;46(11):1708-15. doi: 10.1111/j.1528-1167.2005.00281.x.

PURPOSE

Uncontrolled epilepsy remains a significant health concern and requires new approaches to therapy. N-methyl-d-aspartate (NMDA) receptor blockade has been considered, but the adverse cognitive and behavioral effects of conventional NMDA-receptor antagonists have prevented the development of clinically useful compounds. An alternative approach may be the blockade of the glycine coagonist ("glycine(B)") site of the NMDA receptor.

METHODS

As a first step in the exploration of this approach, we examined the effect of 4-chloro-kynurenine (4-Cl-KYN), which is converted by astrocytes to the potent NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), on the in vivo epileptiform evoked potentials in the CA1 region of rats with chronic limbic epilepsy (CLE). 4-Cl-KYN (100 mg/kg) was administered intraperitoneally to naive and epileptic rats. Evoked potentials were induced in area CA1 of the hippocampus by electrical stimulation of the midline region of the thalamus. Simultaneous microdialysis was performed in the contralateral hippocampus to determine the extracellular levels of 7-Cl-KYNA over the course of the experiment.

RESULTS

Administration of 4-Cl-KYN caused a significant reduction in the amplitude of the population spike and in the number of population spikes in epileptic animals (p < 0.01) but had no effect on the evoked response in naive rats. In contrast, 4-Cl-KYN significantly altered the paired response in naive animals (p < 0.01), but had no significant effect on this parameter in epileptic animals. The levels of 7-Cl-KYNA measured achieved known pharmacologically effective concentrations and paralleled the observed physiological effects.

CONCLUSIONS

The use of glial cells for the neosynthesis and local delivery of neuroactive compounds may be a viable strategy for the treatment of limbic epilepsy. These results also underscore the unique pharmacology of neurons in epilepsy.

目的

未得到控制的癫痫仍是一个重大的健康问题，需要新的治疗方法。N-甲基-D-天冬氨酸（NMDA）受体阻断疗法已被考虑，但传统NMDA受体拮抗剂的不良认知和行为效应阻碍了具有临床应用价值化合物的开发。另一种方法可能是阻断NMDA受体的甘氨酸协同激动剂（“甘氨酸（B）”）位点。

方法

作为探索该方法的第一步，我们研究了4-氯犬尿氨酸（4-Cl-KYN）对慢性边缘性癫痫（CLE）大鼠CA1区体内癫痫样诱发电位的影响，4-氯犬尿氨酸可被星形胶质细胞转化为强效NMDA甘氨酸位点拮抗剂7-氯犬尿喹啉酸（7-Cl-KYNA）。将4-Cl-KYN（100mg/kg）腹腔注射给未患癫痫和患癫痫的大鼠。通过电刺激丘脑中线区域在海马体CA1区诱发诱发电位。在对侧海马体中同时进行微透析，以测定实验过程中7-Cl-KYNA的细胞外水平。

结果

给予4-Cl-KYN可使癫痫动物群体峰电位的幅度和群体峰电位数量显著降低（p<0.01），但对未患癫痫大鼠的诱发反应无影响。相比之下，4-Cl-KYN显著改变了未患癫痫动物的配对反应（p<0.01），但对癫痫动物的该参数无显著影响。所测得的7-Cl-KYNA水平达到了已知的药理有效浓度，并与观察到的生理效应平行。