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.