Cerebral synthesis and release of kynurenic acid: an endogenous antagonist of excitatory amino acid receptors.
Excitatory amino acid (EAA)-mediated synaptic transmission is the most prevalent excitatory system within the mammalian brain. Activation of EAA receptors has been postulated to contribute to neuronal cell death in stroke, epilepsy, hypoglycemia, and Huntington's disease. Kynurenic acid is an endogenous substance that inhibits EAA receptors and may therefore influence important physiologic and pathologic processes. The release of intracerebrally synthesized kynurenic acid into the extracellular fluid (ECF), where it may act at EAA receptors, has not been established in vivo. We studied the synthesis and release of kynurenic acid in the rat striatum using intracerebral microdialysis coupled with high performance liquid chromatography and fluorescence detection. The basal ECF concentration of kynurenic acid in the rat corpus striatum was 17.1 +/- 1.1 nM. Peripheral administration of the immediate biosynthetic precursor of kynurenic acid, L-kynurenine, resulted in marked dose-dependent increases in striatal ECF concentrations of kynurenic acid, peaking at 2-2.5 hr. The highest dose of L-kynurenine (100 mg/kg), administered peripherally, resulted in a 108-fold increase in plasma kynurenic acid levels and a 37-fold increase in cerebral ECF levels. Peripheral administration of kynurenic acid, at a dose that caused plasma levels to increase 430-fold, resulted in only 4-fold increases in striatal ECF concentrations. The precursor responsiveness of striatal ECF kynurenic acid to peripherally infused L-kynurenine was blocked by the central application (via the dialysis probe) of aminooxyacetic acid, an inhibitor of the immediate synthetic enzyme for kynurenic acid, kynurenine aminotransferase. Administration of L-tryptophan was less effective than L-kynurenine in increasing ECF kynurenic acid concentrations and did so at a considerably later time interval (6 hr).(ABSTRACT TRUNCATED AT 250 WORDS)
Swartz
K J
KJ
Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115.
During
M J
MJ
Freese
A
A
Beal
M F
MF
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D007700:Kinetics; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism / Q000494:pharmacology; D008190:Lyases; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D000637:Transaminases / Q000037:antagonists & inhibitors; D014364:Tryptophan / Q000494:pharmacology
D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D000625:Aminooxyacetic Acid; D007737:Kynurenine; D014364:Tryptophan; D000637:Transaminases; C427605:glutamine - phenylpyruvate transaminase; C021481:kynurenine-oxoglutarate transaminase; D008190:Lyases; D007736:Kynurenic Acid