Intravenous administration of L-kynurenine to rhesus monkeys: effect on quinolinate and kynurenate levels in serum and cerebrospinal fluid.
L-Kynurenine was administered intravenously at doses of 25, 75 and 200 mg/kg to 4 rhesus monkeys to examine the acute metabolism of kynurenine to its neuroactive products quinolinate (QUIN) and kynurenate (KYNA). Eleven serum and 6 cerebrospinal fluid (CSF) samples, the latter obtained through indwelling cisternal catheters, were collected periodically for 4 hr after the kynurenine infusion. In both serum and CSF, basal concentration of QUIN exceeded KYNA concentrations several-fold (2715 +/- 356 vs 122 +/- 16 nM in serum and 84 +/- 34 vs 6 +/- 1 nM in CSF). Following kynurenine infusion, QUIN and KYNA levels were elevated in both serum and CSF in proportion to the dose of the bioprecursor. Serum QUIN concentrations increased slowly, reaching a steady-state level of 29 microM 90 min after 200 mg/kg kynurenine. Serum KYNA levels rose more rapidly, peaking within 10 min and gradually declining thereafter (2.8 microM after 4 hr using 200 mg/kg kynurenine). In CSF, both QUIN and KYNA increased steadily, attaining plateau levels of 2.8 and 0.3 microM, respectively, 4 hr after a kynurenine dose of 200 mg/kg. Under all experimental conditions, CSF KYNA levels were substantially lower than CSF QUIN levels. These data show that in non-human primates systematically administered kynurenine can serve as a bioprecursor of QUIN and KYNA in both serum and CSF. Moreover, the results demonstrate qualitative differences in the distribution of de novo synthesized QUIN and KYNA between peripheral and central compartments. The present study also indicates that pharmacological doses of systemically administered kynurenine are not capable of selectively increasing levels of the neuroprotectant KYNA.
Jauch
D A
DA
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228.
Sethy
V H
VH
Weick
B G
BG
Chase
T N
TN
Schwarcz
R
R
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D007262:Infusions, Intravenous; D007736:Kynurenic Acid / Q000097:blood* / Q000134:cerebrospinal fluid*; D007737:Kynurenine / Q000008:administration & dosage*; D008253:Macaca mulatta; D017378:Quinolinic Acid / Q000097:blood* / Q000134:cerebrospinal fluid*; D013997:Time Factors
D007737:Kynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid