Quinolinic acid — Iron(II) complexes: Slow autoxidation, but enhanced hydroxyl radical production in the Fenton reaction

Abstract

Quinolinate (pyridine-2,3-dicarboxylic acid, Quin) is a neurotoxic tryptophan metabolite produced mainly by immune-activated macrophages. It is implicated in the pathogenesis of several brain disorders including HIV-associated dementia. Previous evidence suggests that Quin may exert its neurotoxic effects not only as an agonist on the NMDA subtype of glutamate receptor, but also by a receptor-independent mechanism. In this study we address ability of ferrous quinolinate chelates to generate reactive oxygen species. Autoxidation of Quin-Fe(II) complexes, followed in Hepes buffer at pH 7.4 using ferrozine as the Fe(II) detector, was found to be markedly slower in comparison with iron unchelated or complexed to citrate or ADP. The rate of Quin-Fe(II) autoxidation depends on pH (squared hydroxide anion concentration), is catalyzed by inorganic phosphate, and in both Hepes and phosphate buffers inversely depends on Quin concentration. These observations can be explained in terms of anion catalysis of hexaaquairon(II) autoxidation, acting mainly on the unchelated or partially chelated pool of iron. In order to follow hydroxyl radical generation in the Fenton chemistry, electron paramagnetic resonance (EPR) spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) was employed. In the mixture consisting of 100 mM DMPO, 0.1 mM Fe(II), and 8.8 mM hydrogen peroxide in phosphate buffer pH 7.4, 0.5 mM Quin approximately doubled the yield of DMPO-OH adduct, and higher Quin concentration increased the spin adduct signal even more. When DMPO-OH was pre-formed using Ti3+ /hydrogen peroxide followed by peroxide removal with catalase, only addition of Quin-Fe(II), but not Fe(II), Fe(III), or Quin-Fe(III), significantly promoted decomposition of pre-formed DMPO-OH. Furthermore, reaction of Quin-Fe(II) with hydrogen peroxide leads to initial iron oxidation followed by appearance of iron redox cycling, detected as slow accumulation of ferrous ferrozine complex. This phenomenon cannot be abolished by subsequent addition of catalase. Thus, we propose that redox cycling of iron by a Quin derivative, formed by initial attack of hydroxyl radicals on Quin, rather than effects of iron complexes on DMPO-OH stability or redox cycling by hydrogen peroxide, is responsible for enhanced DMPO-OH signal in the presence of Quin. The present observations suggest that Quin-Fe(II) complexes display significant pro-oxidant characteristics that could have implications for Quin neurotoxicity.

Quinolinic acid induces NMDA receptor-mediated lipid peroxidation in rat brain microvessels

“…19 The results of the present study strongly imply that QUIN can, indeed, cause lipid peroxidation in brain microvessels. There could be regional variations in the exact mechanism of the action of QUIN: in comparison to hippocampus and the entorhinal cortex, the lipid peroxidation in the striatum was less sensitive to the NMDA-R antagonist D-2-APV, possibly suggesting the presence of an NMDA-R independent component of the mechanism (Table 1; see Pláteník et al 20 for an example of such mechanism).…”

Involvement of quinolinic acid in aids dementia complex

“…However, some studies have indicated that QUIN forms a complex with iron, and electron transfer from this complex to oxygen results in the formation of reactive oxygen species which mediate lipid peroxidation (Goda et al, 1996;Stipek et al, 1997). QUIN-Fe(II) complexes display significant pro-oxidant characteristics that could have implications for QUIN neurotoxicity (Platenik et al, 2001). This may partly account for the protective effect of antioxidants on excitotoxic insults (Nakao et al, 1996).…”

Essential Oil from Lemon Peels Inhibit Key Enzymes Linked to Neurodegenerative Conditions and Pro-oxidant Induced Lipid Peroxidation

“…Similarly, the incubation of rat s brain homogenates in presence of quinolinic acid caused a significant increase in the MDA content due to increased lipid peroxidation brought about by the ability of quinolinic acid to form complexes which induce excess free radical formation 44 .…”