Immunohistochemical visualization of newly formed quinolinate in the normal and excitotoxically lesioned rat striatum.
Intracerebral infusion of 3-hydroxyanthranilate (3HANA) rapidly increases the brain content of the endogenous excitotoxin quinolinate (QUIN). QUIN formation from 3HANA is readily prevented by coadministration of the specific 3-hydroxyanthranilate oxygenase inhibitor 4-chloro-3HANA (4-Cl-3HANA). This experimental paradigm was used to identify the cell populations which are responsible for the rapid de novo production of QUIN in the rat striatum in vivo. Rats received an intrastriatal infusion of 3HANA, alone or together with equimolar 4-Cl-3HANA, for 1 h. Striatal QUIN immunoreactivity (ir) was assessed immunohistochemically, using an antibody against protein-conjugated QUIN. This antibody displayed no significant crossreactivity with compounds structurally or functionally related to QUIN. QUIN-ir cells were detected after infusion with > or =300 microM 3HANA, but not in naïve striata or after co-infusion of 4-Cl-3HANA. Cellular staining was also abolished by preabsorption of the antibody with protein-conjugated QUIN. In the normal striatum, QUIN-ir was detected exclusively in cells of an apparent microglial morphology. When examined in the excitotoxically lesioned striatum, 3HANA-induced QUIN-ir localized exclusively to OX42-ir cells of an activated microglial/macrophage morphology. These data indicate that microglia and macrophages are the major source of QUIN in the rat striatum when hyperphysiological concentrations of 3HANA are used to drive QUIN synthesis. Comparison with earlier biochemical and immunohistochemical studies suggests that the enzyme responsible for microglial QUIN production is a distinct 3-hydroxyanthranilate oxygenase with high capacity and low affinity for 3HANA.
Lehrmann
E
E
Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA.
Molinari
A
A
Speciale
C
C
Schwarcz
R
R
D015095:3-Hydroxyanthranilic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004338:Drug Combinations; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D004338:Drug Combinations; D009498:Neurotoxins; D015095:3-Hydroxyanthranilic Acid; C026381:4-chloro-3-hydroxyanthranilic acid; D017378:Quinolinic Acid