Studies on the disposition of quinolinic acid after intracerebral or systemic administration in the rat.
Quinolinic acid (QUIN) is an endogenous, excitotoxic amino acid which is currently under investigation as a possible etiological factor in human neurodegenerative disorders such as Huntington's disease and epilepsy. We explored certain aspects of this hypothesis, using the adult rat as an experimental animal. After intrastriatal infusions of [3H]QUIN, radioactivity was cleared from the injected region with an apparent half-life of 22 min. To 2 h after injection, all radioactivity recovered from the striatum corresponded to unmetabolized QUIN. Consistent with these data was the lack of significant uptake of [3H]QUIN by slices or crude synaptosomes prepared from rat hippocampus or striatum. When applied intravenously, a high dose of QUIN (450 mg/kg) caused relatively minor seizure-related EEG changes and no signs of neuronal degeneration. Direct measurements indicated negligible penetration of the blood-brain barrier by QUIN. The lack of an effective inactivation mechanism for extracellular QUIN in the brain negates QUIN's proposed role as a classical neurotransmitter substance, but may be of significance for the postulated effects of this compound in neurodegenerative diseases. An important role of blood-borne QUIN or QUIN precursors in human disorders cannot be ruled out at present; although the brain appears to be well protected by the blood-brain barrier from an acute elevation of blood QUIN, a possible breakdown of the barrier under pathologic conditions and the effects of chronic elevations of blood QUIN remain to be examined.
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier; D003342:Corpus Striatum / Q000378:metabolism; D004569:Electroencephalography; D066298:In Vitro Techniques; D007267:Injections; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D008297:Male; D011725:Pyridines / Q000008:administration & dosage*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D011725:Pyridines; D011805:Quinolinic Acids; D017378:Quinolinic Acid