Quinolinic acid in vivo synthesis rates, extracellular concentrations, and intercompartmental distributions in normal and immune-activated brain as determined by multiple-isotope microdialysis.
Quinolinic acid (QUIN) kills neurons by activation of NMDA receptors that are accessed via the extracellular fluid (ECF). In vivo microdialysis was employed to quantify the dynamics of ECF QUIN levels. [(13)C7]QUIN was perfused through the probe for in vivo calibration to accurately quantify ECF QUIN concentrations. Osmotic pumps infused [(2H)3]QUIN subcutaneously to quantify blood contributions to ECF and tissue levels. Local QUIN production rates and influx and efflux rates across the blood-brain barrier were calculated from the extraction fraction of [(13)C7]QUIN, probe geometry, tissue diffusion coefficients, the extracellular volume fraction, and [(2)H3]QUIN/QUIN ratios in blood and dialysates. In normal brain, 85% of ECF QUIN levels (110 nM) originated from blood, whereas 59% of tissue homogenate QUIN (130 pmol/g) originated from local de novo synthesis. During systemic immune activation (intraperitoneal injection of endotoxin), blood QUIN levels increased (10.2-fold) and caused a rise in homogenate (10.8-fold) and ECF (18.5-fold) QUIN levels with an increase in the proportions of QUIN derived from blood. During CNS inflammation (local infusion of endotoxin), increases in brain homogenate (246-fold) and ECF (66-fold) QUIN levels occurred because of an increase in local synthesis rate (146-fold) and a reduction in efflux/influx ratio (by 53%). These results demonstrate that brain homogenate measures are a reflection of ECF concentrations, although there are quantitative differences in the values obtained. The mechanisms that maintain ECF QUIN levels at low values cannot do so when there are large increases in local brain synthesis or when there are large elevations in blood QUIN concentrations.
Beagles
K E
KE
Laboratory of Neurotoxicology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1262, USA.
Morrison
P F
PF
Heyes
M P
MP
D000287:Administration, Topical; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000276:immunology* / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004679:Encephalomyelitis / Q000139:chemically induced / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D005849:Gerbillinae; D007107:Immune System / Q000502:physiology*; D007274:Injections, Intraperitoneal; D007554:Isotopes; D017551:Microdialysis / Q000379:methods; D009994:Osmolar Concentration; D017378:Quinolinic Acid / Q000378:metabolism*; D012016:Reference Values; D014018:Tissue Distribution
D004731:Endotoxins; D007554:Isotopes; D017378:Quinolinic Acid