In vivo hydroxyl radical formation after quinolinic acid infusion into rat corpus striatum

Abstract

We studied the effect of an acute infusion of quinolinic acid (QUIN) on in vivo hydroxyl radical (.OH) formation in the striatum of awake rats. Using the microdialysis technique, the generation of.OH was assessed through electrochemical detection of the salicylate hydroxylation product 2,3-dihydroxybenzoic acid (2,3-DHBA). The .OH extracellular levels increased up to 30 times over basal levels after QUIN infusion (240 nmol/microl), returning to the baseline 2 h later. This response was attenuated, but not abolished, by pretreatment with the NMDA receptor antagonist MK-801 (10 mg/kg, i.p.) 60 min before QUIN infusion. The mitochondrial toxin 3-nitropropionic acid (3-NPA, 500 nmol/microl) had stronger effects than QUIN on .OH generation, as well as on other markers of oxidative stress explored as potential consequences of .OH increased levels. These results support the hypothesis that early .OH generation contributes to the pattern of toxicity elicited by QUIN. The partial protection by MK-801 suggests that QUIN neurotoxicity is not completely explained through NMDA receptor overactivation, but it may also involve intrinsic QUIN oxidative properties.

Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis

“…QUIN leads to the ROS formation in neurons [90,91] and one of the major aspects of QUIN toxicity is lipid peroxidation [18][19][20][21] . In synaptosomes from rat brain, lipid peroxidation has been shown to be increased by 256% after injection of QUIN 100 M [92] .…”

“…pending of its concentration, QUIN can lead to acute neuronal death or to chronic and progressive neuronal dysfunction by at least four mechanisms: (1) it can activate the NMDA receptor in pathophysiological concentrations leading to an increase of intracellular calcium [16] ; (2) QUIN can increase glutamate release by neurons and inhibit its uptake into the synaptic vesicle by astrocytes leading to excessive microenvironment glutamate concentrations and neurotoxicity [17] ; (3) QUIN can lead to signifi cant lipid peroxidation [18][19][20][21] , and lastly (4) QUIN can potentiate its own toxicity and that of other excitotoxins (e.g. NMDA and glutamate) in the context of energy depletion [22,23] .…”

Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-d-aspartate neurotoxicity

“…We also examined if the d-Amph-induced reduction in KYNA levels was accompanied by an increased production of 3-HK and/or QUIN in the competing branch of the kynurenine pathway. By forming reactive free radicals and acting synergistically (Eastman and Guilarte, 1990;Guidetti and Schwarcz, 1999;Santamaria et al, 2001), a rapid up-regulation of 3-HK or QUIN synthesis could exacerbate NMDA receptormediated neurotoxicity, providing a simple alternative explanation for the potentiation of lesion size by d-Amph. However, both 3-HK and QUIN levels in the striatum were unaffected by dAmph, and the free radical scavenger IPA failed to attenuate the enhanced neurotoxicity.…”

The Pivotal Neuroinflammatory, Therapeutic and Neuroprotective Role of Alpha-Mangostin

“…These activities above incriminate mitochondrial dysfunction and oxidative stress in neurodegenerative disorders [129,132,133]. Several authors [129,134,135] have established that the production of ROS like superoxide anion (O 2 •-), hydroxyl radicals (OH • ), and cellular oxidative mutilation occurs in rat striatum after inoculation of 3-NP. Interestingly, oxidative mutilation and the size of the striatal lesion triggered via 3-NP are decreased after antioxidant inoculation [129,136].…”