Dose Of Quinolinic Acid Research Articles

Effect of quinolinic acid – A uremic toxin from tryptophan metabolism – On hemostatic profile in rat and mouse thrombosis models

PurposeWe aimed to determine the effect of quinolinic acid (QA) on hemostasis in rat and mouse models of thrombosis. Material and methodsWistar rats (male, n = 72) received QA dissolved in drinking water in doses of 3, 10, 30 mg/kg or pure drinking water (vehicle control group -VEH) for 14 days. On the 14th day of the experiment the effect of QA on hemostasis was evaluated using electrically induced arterial thrombosis model. The following parameters were measured: thrombus weight, hematology, thromboelastometric (ROTEM) parameters, TXA2 and 6-keto-PGF1α concentration, coagulation and fibrinolytic markers activity and concentration.GFP mice (male, n = 30) were assigned to the group receiving QA (30 mg/kg) or VEH for 14 days and to the group receiving: single intravenous dose of QA (30 mg/kg) or VEH or the same dose of QA and anti-CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1) antibody conjugated with Alexa Fluor 647. The effect of QA on hemostasis was evaluated in the model of laser-induced injury of mesentery vein using intravital confocal microscopy. ResultsAdministering QA for 14 days resulted in a divergent, depending on dose, increase in concentration of active form of tPA and PAI-1 and concentration of total PAI-1 and PAP complexes in rats’ plasma. In turn, administering QA for 14 days in mice revealed its prothrombotic activity, while single-dose IV administration revealed its antithrombotic activity, through the up-regulation of PECAM-1 expression. ConclusionsWe demonstrated the first evidence for the opposite biological effects of QA on hemostasis in rat and mouse thrombosis models.

Maintenance of Susceptibility to Neurodegeneration Following Intrastriatal Injections of Quinolinic Acid in a New Transgenic Mouse Model of Huntington's Disease

A transgenic mouse model of Huntington's disease (R6/1 and R6/2 lines) expressing exon 1 of the HD gene with 115-150 CAG repeats resisted striatal damage following injection of quinolinic acid and other neurotoxins. We examined whether excitotoxin resistance characterizes mice with mutant huntingtin transgenes. In a new transgenic mouse with 3 kb of mutant human huntingtin cDNA with 18, 46, or 100 CAG repeats, we found no change in susceptibility to intrastriatal injections of the excitotoxin quinolinic acid, compared to wild-type littermates. The new transgenic mice were injected with the same dose of quinolinic acid (30 nmol) as had been the R6 mice. Our findings highlight the importance of studying pathogenetic mechanisms in different transgenic models of a disease.

Metabolic changes in quinolinic acid-lesioned rat striatum detected non-invasively by in vivo (1)H NMR spectroscopy.

Intrastriatal injection of quinolinic acid (QA) provides an animal model of Huntington disease. In vivo (1)H NMR spectroscopy was used to measure the neurochemical profile non-invasively in seven animals 5 days after unilateral injection of 150 nmol of QA. Concentration changes of 16 metabolites were measured from 22 microl volume at 9.4 T. The increase of glutamine ((+25 +/- 14)%, mean +/- SD, n = 7) and decrease of glutamate (-12 +/- 5)%, N-acetylaspartate (-17 +/- 6)%, taurine (-14 +/- 6)% and total creatine (-9 +/- 3%) were discernible in each individual animal (P < 0.005, paired t-test). Metabolite concentrations in control striata were in excellent agreement with biochemical literature. The change in glutamate plus glutamine was not significant, implying a shift in the glutamate-glutamine interconversion, consistent with a metabolic defect at the level of neuronal-glial metabolic trafficking. The most significant indicator of the lesion, however, were the changes in glutathione ((-19 +/- 9)%, P < 0.002)), consistent with oxidative stress. From a comparison with biochemical literature we conclude that high-resolution in vivo (1)H NMR spectroscopy accurately reflects the neurochemical changes induced by a relatively modest dose of QA, which permits one to longitudinally follow mitochondrial function, oxidative stress and glial-neuronal metabolic trafficking as well as the effects of treatment in this model of Huntington disease.

Age-Dependent Differences in Survival of Striatal Somatostatin–NPY–NADPH–Diaphorase-Containing Interneurons versus Striatal Projection Neurons after Intrastriatal Injection of Quinolinic Acid in Rats

Some authors have reported greater sparing of neurons containing somatostatin (SS)–neuropeptide Y (NPY)–NADPH-diaphorase (NADPHd) than projection neurons after intrastriatal injection of quinolinic acid (QA), an excitotoxin acting at NMDA receptors. Such findings have been used to support the NMDA receptor excitotoxin hypothesis of Huntington's disease (HD) and to claim that intrastriatal QA produces an animal model of HD. Other studies have, however, reported that SS/NPY/NADPHd interneurons are highly vulnerable to QA. We examined the influence of animal age (young versus mature), QA concentration (225 mMversus 50 mM), and injection speed (3 min versus 15 min) on the relative SS/NPY/NADPHd neuron survival in eight groups of rats that varied along these parameters to determine the basis of such prior discrepancies. Two weeks after QA injection, we analyzed the relative survival of neurons labeled by NADPHd histochemistry, SS/NPY immunohistochemistry, or cresyl violet staining (which stains all striatal neurons, the majority of which are projection neurons) in the so-called lesion transition zone (i.e., the zone of 40–60% neuronal survival). We found that age, and to a lesser extent injection speed, had a significant effect on relative SS/NPY/NADPHd interneuron survival. The NADPHd- and SS/NPY-labeled neurons typically survived better than projection neurons in young rats and more poorly in mature rats. This trend was greatly accentuated with fast QA injection. Age-related differences may be attributable to declines in projection neuron sensitivity to QA with age. Since rapid QA injections result in excitotoxin efflux, we interpret the effect of injection speed to suggest that brief exposure to a large dose of QA (with fast injection) may better accentuate the differential vulnerabilities of NADPHd/SS/NPY interneurons and projection neurons than does exposure to the same total amount of QA delivered more gradually (slow injection). These findings reconcile the discordant results found by previous authors and suggest that QA injected into rat striatum does reproduce the neurochemical traits of HD under some circumstances. These findings are consistent with a role of excitotoxicity in HD pathogenesis, and they also have implications for the basis of the more pernicious nature of striatal neuron loss in juvenile onset HD.

β-Amyloid 25–35 and/or quinolinic acid injections into the basal forebrain of young male Fischer-344 rats: Behavioral, neurochemical and histological effects

β-Amyloid peptides have been shown to potentiate the neurotoxic effect of excitatory amino acids in vitro. In order to determine if this occurs in vivo, four experiments were performed. We injected β-amyloid 25–35 (βA 25–35) and/or quinolinic acid (QA) bilaterally into the ventral pallidum/substantia innominata (VP/SI) of rats. Control rats received vehicle infusions. A high dose of QA (75.0 nmol/3 μl) increased open field activity and impaired spatial learning in the Morris water maze, but did not affect the acquisition of a one-way conditioned avoidance response. These changes were associated with histological evidence of neurotoxicity and a reduction in amygdaloid but not frontal cortical or hippocampal choline acetyltransferase (ChAT) activity. A lower dose of QA (37.5 nmol/3 μl) produced no behavioral effects. It reduced amygdaloid ChAT activity to a lesser extent than the higher dose (15% vs. 29–37%), and caused less histological damage. βA 25–35 (1.0 or 8.0 nmol/3 μl) failed to produce behavioral, histological or neurochemical signs of toxicity. Neither dose of βA 25–35 potentiated the effects of QA (37.5 nmol) on behavior or amygdaloid ChAT activity, and did not appear to increase the histological damage caused by QA. These results suggest that in vivo βA 25–35 is not neurotoxic and does not potentiate the neurotoxicity of QA in the VP/SI. Further, the histological effects of a high dose of βA 25–35 (8.0 nmol/3 μl; a cavitation containing a Congo red positive proteinaceous material) are quite distinct from those produced by a high dose of QA (75.0 nmol/3 μl; widespread neuronal loss and gliosis).

Nerve growth factor and basic fibroblast growth factor protect cholinergic neurons against quinolinic acid excitotoxicity in rat neostriatum.

In the present work we have characterized a possible mechanism leading to the early survival of neostriatal cholinergic neurons after quinolinic acid injection. Different doses of quinolinic acid were injected in rat neostriatum and two different parameters were analysed 7 days after the lesion: choline acetyltransferase (ChAT) activity and nerve growth factor (NGF) levels. We have observed that ChAT activity decreased (until 68 nmol quinolinic acid) and NGF levels increased (until 34 nmol quinolinic acid) in a dose-dependent manner. In order to characterize the time-course of the lesion on NGF levels and ChAT activity, and the possible protective effect of NGF and basic fibroblast growth factor (bFGF) on cholinergic neurons, we have used the quinolinic acid dose (68 nmol) at which the first decrease of ChAT activity was observed. ChAT activity and NGF levels showed different patterns of response to quinolinic acid injection, since the maximal effect was reached at 1 day for ChAT activity and at 2 days for NGF levels. NGF or bFGF simultaneously injected with quinolinic acid (68 nmol) completely prevented the decrease in ChAT activity in a dose-dependent manner but NGF was more effective than bFGF. Furthermore, differences observed in ChAT activity after NGF but not bFGF treatment were correlated with changes in the number of ChAT immunoreactive cells. Finally, we have also observed that, although bFGF alone was not able to modify NGF levels, bFGF simultaneously injected with quinolinic acid produced an increase of NGF levels higher than that observed after quinolinic acid injection alone.(ABSTRACT TRUNCATED AT 250 WORDS)

The quinolinic acid model of Huntington's disease: Locomotor abnormalities

In contrast to other excitotoxins, such as kainic acid, quinolinic acid (QA) may spare a specific population of striatal neurons that is also spared in Huntington's disease (HD). Although several histological and biochemical experiments support the use of QA as a model for HD, to date no behavioral experiments have been performed to examine the suitability of this model. The present study explored the behavioral effects of bilateral intrastriatal microinjections of four doses (75, 150, 225, 300 nmol) of QA in the male rat. Using a multidimensional analysis of spontaneous locomotion (Digiscan activity) and a record of metabolic indicators, such as weight loss, a dose-dependent effect was found. The 75-nmol dose had no significant effect on locomotion or feeding behavior. In contrast, the 150- and 225-nmol doses induced hyperactivity and weight loss, whereas the 300-nmol dose was lethal. The results obtained suggest that striatal injections of 150–225 nmol of QA induce behavioral deficits qualitatively similar though quantitatively less than those which are seen after similar injection of 3 nmol of kainic acid and which have been reported to be comparable to the symptomatology of HD. Together with QA's possible greater histological selectivity, the present results support the use of QA-induced striatal lesions as a behavioral model of Huntington's disease.

“In vivo” studies on the interactions between excitotoxins and gangliosides

In contrast to other excitotoxins, such as kainic acid, quinolinic acid (QA) may spare a specific population of striatal neurons that is also spared in Huntington's disease (HD). Although several histological and biochemical experiments support the use of QA as a model for HD, to date no behavioral experiments have been performed to examine the suitability of this model. The present study explored the behavioral effects of bilateral intrastriatal microinjections of four doses (75, 150, 225, 300 nmol) of QA in the male rat. Using a multidimensional analysis of spontaneous locomotion (Digiscan activity) and a record of metabolic indicators, such as weight loss, a dose-dependent effect was found. The 75-nmol dose had no significant effect on locomotion or feeding behavior. In contrast, the 150- and 225-nmol doses induced hyperactivity and weight loss, whereas the 300-nmol dose was lethal. The results obtained suggest that striatal injections of 150–225 nmol of QA induce behavioral deficits qualitatively similar though quantitatively less than those which are seen after similar injection of 3 nmol of kainic acid and which have been reported to be comparable to the symptomatology of HD. Together with QA's possible greater histological selectivity, the present results support the use of QA-induced striatal lesions as a behavioral model of Huntington's disease.