In situ-produced 7-chlorokynurenate has different effects on evoked responses in rats with limbic epilepsy in comparison to naive controls.
OBJECTIVE
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.
Zhang
De Xing
DX
Department of Neurology, University of Virginia, Charlottesville, Virginia 22908-0394, USA. ehb2z@virginia.edu
Williamson
John M
JM
Wu
Hu-Qui
HQ
Schwarcz
Robert
R
Bertram
Edward H
EH
D000818:Animals; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D004827:Epilepsy / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D005071:Evoked Potentials / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid