Kynurenate and 7-chlorokynurenate formation in chronically epileptic rats.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Wu
Hui-Qiu
HQ
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, U.S.A.
Rassoulpour
Arash
A
Goodman
Jeffrey H
JH
Scharfman
Helen E
HE
Bertram
Edward H
EH
Schwarcz
Robert
R
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000378:metabolism; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism*; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism* / Q000494:pharmacology; D005911:Gliosis / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid