title: Regulation of quinolinic acid neosynthesis in mouse, rat and human brain by iron and iron chelators in vitro.
abstract: Several lines of evidence indicate that excess iron may play an etiologically significant role in neurodegenerative disorders. This idea is supported, for example, by experimental studies in animals demonstrating significant neuroprotection by iron chelation. Here, we tested whether this effect might be related to a functional link between iron and the endogenous excitotoxin quinolinic acid (QUIN), a presumed pathogen in several neurological disorders. In particular, the present in vitro study was designed to examine the effects of Fe(2+), a known co-factor of oxygenases, on the activity of QUIN's immediate biosynthetic enzyme, 3-hydroxyanthranilic acid dioxygenase (3HAO), in the brain. In crude tissue homogenate, addition of Fe(2+) (2-40 μM) stimulated 3HAO activity 4- to 6-fold in all three species tested (mouse, rat and human). The slope of the iron curve was steepest in rat brain where an increase from 6 to 14 μM resulted in a more than fivefold higher enzyme activity. In all species, the Fe(2+)-induced increase in 3HAO activity was dose-dependently attenuated by the addition of ferritin, the main iron storage protein in the brain. The effect of iron was also readily prevented by N,N'-bis(2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED), a synthetic iron chelator with neuroprotective properties in vivo. All these effects were reproduced using neostriatal tissue obtained postmortem from normal individuals and patients with end-stage Huntington's disease. Our results suggest that QUIN levels and function in the mammalian brain might be tightly controlled by endogenous iron and proteins that regulate the bioavailability of iron.
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, Maryland 21228, USA.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Stachowski
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
mesh_terms: D000328:Adult; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008875:Middle Aged; D017378:Quinolinic Acid / Q000138:chemical synthesis* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007502:Iron Chelating Agents; D007501:Iron; D017378:Quinolinic Acid