Quantitative differences in the effects of de novo produced and exogenous kynurenic acid in rat brain slices.
Kynurenic acid (KYNA) is an antagonist of (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors and it blocks the glycine site of the NMDA receptor preferentially (IC50 = 7.9 microM). KYNA is produced endogenously by transamination of its precursor L-kynurenine (L-KYN). We tested the hypothesis that effects of endogenous, de novo produced KYNA, following bath-application of L-KYN to slices, would be different than effects of commercially-synthesized (exogenous) KYNA. The ability to block spontaneous epileptiform activity, induced by lowering extracellular magnesium, was examined in area CA3 of hippocampus and the entorhinal cortex. At a concentration of 200 microM L-KYN, which produced 0.89 +/- 0.20 microM KYNA, there were fewer slices with spontaneous epileptiform activity than slices exposed to 2 microM exogenous KYNA. The results indicate a more potent neuromodulatory action of endogenous KYNA than has been previously realized.
Scharfman
H E
HE
Neurology Research Center, Helen Hayes Hospital, West Haverstraw, NY 10993-1195, USA. helensch@mindspring.com
Hodgkins
P S
PS
Lee
S C
SC
Schwarcz
R
R
D000818:Animals; D002021:Buffers; D018728:Entorhinal Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy; D005071:Evoked Potentials / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007736:Kynurenic Acid / Q000378:metabolism* / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000494:pharmacology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D014364:Tryptophan / Q000378:metabolism
D002021:Buffers; D018691:Excitatory Amino Acid Antagonists; D018377:Neurotransmitter Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014364:Tryptophan; D007736:Kynurenic Acid; D008274:Magnesium; D005998:Glycine