Quinolinic acid is extruded from the brain by a probenecid-sensitive carrier system: a quantitative analysis.
Although the neurotoxic tryptophan-kynurenine pathway metabolite quinolinic acid originates in brain by both local de novo synthesis and entry from blood, its concentrations in brain parenchyma, extracellular fluid, and CSF are normally below blood values. In the present study, an intraperitoneal injection of probenecid (400 mg/kg), an established inhibitor of acid metabolite transport in brain, into gerbils, increased quinolinic acid concentrations in striatal homogenates, CSF, serum, and homogenates of kidney and liver. Direct administration of probenecid (10 mM) into the brain compartment via an in vivo microdialysis probe implanted into the striatum also caused a progressive elevation in both quinolinic acid and homovanillic acid concentrations in the extracellular fluid compartment but was without effect on serum quinolinic acid levels. A model of microdialysis transport showed that the elevations in extracellular fluid quinolinic acid and homovanillic acid levels following intrastriatal application are consistent with probenecid block of a microvascular acid transport mechanism. We conclude that quinolinic acid in brain is maintained at concentrations below blood levels largely by active extrusion via a probenecid-sensitive carrier system.
Morrison
P F
PF
Bioengineering and Physical Science Program, Office of Research Services, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1262, USA.
Morishige
G M
GM
Beagles
K E
KE
Heyes
M P
MP
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D003198:Computer Simulation; D003342:Corpus Striatum / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005849:Gerbillinae; D006719:Homovanillic Acid / Q000378:metabolism; D008954:Models, Biological; D009994:Osmolar Concentration; D011339:Probenecid / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000097:blood / Q000378:metabolism*
D002352:Carrier Proteins; D017378:Quinolinic Acid; D011339:Probenecid; D006719:Homovanillic Acid