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PubMed1988

[Selective anticonvulsive action of N-substituted imidazole-4,5-dicarboxylic acids against quinolinic acid].

Selective antagonists of quinolinic acid (2,3-pyridine dicarboxylic acid, QUIN)--an endogenous convulsant tryptophan metabolite, administered intracerebroventricular to mice, were identified during comparison with the following intracerebroventricular convulsants: l-kynurenine, aspartic, glutamic, N-methyl-DL-aspartic and kainic acids. It is suggested that the antagonism arises due to a common fragment of the structure which consists of two carboxylic groups at two nearest carbon atoms of the ring and of one nitrogen atom in the alpha-position. The selective action of the compounds found against QUIN supports the suggestion that QUIN produces seizures via N-methyl-D-aspartate binding sites.

Animals↗
PubMed1997

Differential responses of extracellular GABA to intrastriatal perfusions of 3-nitropropionic acid and quinolinic acid in the rat.

Although both quinolinic acid and 3-nitropropionic acid destroy medium sized, GABAergic, spiny projection neurons after direct perfusion of neurotoxin into the rat striatum, changes in extracellular GABA concentration in the striatum within the first 90 min reflect different toxic mechanisms in these two animal models for Huntington's disease. Since quinolinic acid acts as a potent excitotoxin, the early depolarizing response in GABAergic neurons results in an early increase in extracellular GABA activity (peak at 40 min) whereas the more indirect action of 3-nitropropionic acid on mitochondrial energy metabolism results in a delayed increase in extracellular GABA activity (peak at 60 min) with a pattern of gradual increase and decline. The localized delivery of cytotoxin provides an opportunity for kinetic comparisons of direct and indirect cytotoxic mechanisms that can be useful in developing neuroprotective treatment strategies in Huntington's disease.

Animals↗
PubMed1987

Effects of 2,4,5-trichlorophenoxyacetic acid and quinolinic acid on 5-hydroxy-3-indoleacetic acid transport by the rabbit choroid plexus: pharmacology and electron microscopic cytochemistry.

2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) reduced the uptake of 5-hydroxy-3-indoleacetic acid (5-HIAA) by the choroid plexus in a dose-related manner, while treatment with quinolinic acid at comparable concentrations did not inhibit 5-HIAA uptake. The role of carrier-mediated transport in the clearance of 5-HIAA from cerebrospinal fluid (CSF) was also evaluated in vivo by ventriculocisternal perfusion. Steady-state clearance of 5-HIAA from CSF exceeded that of inulin and was reduced competitively in the presence of 2,4,5-T. However, the clearance was not affected by quinolinic acid. The effect of 2,4,5-T on transport enzyme systems was also studied by electron microscopic cytochemistry. Na+-K+-ATPase and cytochrome oxidase activities in the choroid plexus were reduced by 2,4,5-T. Since this transport system in the choroid plexus is normally responsible for the excretion of the serotonin metabolite from the brain to the plasma, accumulation of endogenously produced organic acids in the CSF and the brain, secondary to reduced clearance by the choroid plexus, could be a contributing factor in the development of neurotoxicity.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1989

Alteration of kainic acid and quinolinic acid toxicity by neostriatal transplants in vitro.

Mature (greater than 21 days in vitro) organotypic corticostriatal cultures prepared from newborn rat brain were incubated in either kainic acid (KA) 10(-3) M or quinolinic acid (QUIN) 10(-3) M for up to 48 h. Other identical cultures were similarly incubated immediately after they had received one or two additional explants of neonatal striatal tissue placed beside each corticostriatal culture. The cultures incubated with either KA or QUIN in the presence of the neonatal striatal tissue showed better preservation than cultures incubated with KA or QUIN alone. Results suggest that the neonatal striatal explants or 'transplants' afford some protective effect against the toxicity or either KA or QUIN.

Animals↗
PubMed1985

Actions of kynurenic acid and quinolinic acid in the rat hippocampus in vivo.

An iontophoretic study was made of the interaction of kynurenic acid with excitatory amino acids in the hippocampus and with the commissural input from the contralateral hippocampus in the rat. The results showed that kynurenic acid was an effective blocker of synaptic transmission in the hippocampus in vivo, adding further support to the idea that an excitatory amino acid is involved in neurotransmission in this structure. In addition there was an increase in the specificity of kynurenate as an antagonist of excitatory amino acids in the hippocampus compared with neocortex, with much more activity being shown toward the NMDA-preferring rather than the quisqualic acid-preferring receptor. Kynurenic acid was also able to distinguish partially between quinolinic acid and NMDA, supporting the possibility that two types of NMDA/quinolinate receptors exist in the hippocampus.

Amino Acids↗
PubMed1986

Kynurenic acid and quinolinic acid act at N-methyl-D-aspartate receptors in the rat hippocampus.

Responses evoked by several amino acid excitants, including the tryptophan metabolite quinolinic acid, were recorded intracellularly from CA1 pyramidal neurons in rat hippocampal slices. Quinolinate, N-methyl-D-aspartate (NMDA), ibotenate and (+/-)-cis-1-amino-1,3-dicarboxycyclopentane produced excitations characterized by burst firing of action potentials, tetrodotoxin-resistant spiking and apparent increases in input resistance measured with brief hyperpolarizing current pulses. L-Glutamate, kainate, quisqualate and (+/-)-2'-amino-3-hydroxy-5-methyl-4-isoxazole-3'-propionate depolarized CA1 pyramidal neurons and induced apparent decreases in input resistance. Quinolinate-, NMDA-, and ibotenate-induced focal depolarizations, but not L-glutamate, kainate- or quisqualate-induced responses, were strongly antagonized by specific NMDA receptor antagonists. The tryptophan metabolite kynurenic acid, at concentrations that antagonized focal depolarizations produced by NMDA, ibotenate and the endogenous excitant quinolinate, did not antagonize quisqualate or L-glutamate responses. In addition to its NMDA-type antagonist action, kynurenate blocked kainate-induced focal depolarizations.

Animals↗
PubMed1986

Ca2+-dependent depolarization and burst firing of rat CA1 pyramidal neurones induced by N-methyl-D-aspartic acid and quinolinic acid: antagonism by 2-amino-5-phosphonovaleric and kynurenic acids.

The excitatory effects of microiontophoretically applied quisqualic (QUIS), N-methyl-D-aspartic (NMDA), and quinolinic (QUIN) acids were investigated using intracellular recording from CAl pyramidal neurones in slices of rat hippocampus. QUIS evoked only simple action potentials superimposed upon a depolarization which attained a clear plateau. When this level had been reached, increased ejecting currents did not produce further depolarization. By contrast, with low currents NMDA and QUIN elicited small membrane depolarizations which triggered bursts of action potentials superimposed upon rhythmically occurring depolarizing shifts. Larger currents caused depolarization which if sufficiently large completely blocked spike activity. Tetrodotoxin (TTX) prevented the spikes evoked by QUIS and the bursts of action potentials seen with NMDA and QUIN, and the rhythmic depolarizing shifts then appeared as broad spikes of up to 50 mV in amplitude. These and the underlying membrane depolarization were blocked by Co2+, by the NMDA antagonist D(-)-2-amino-5-phosphonovaleric acid (DAPV), and by kynurenic acid (KYNU). It thus appears that the depolarization and burst firing of rat CAl pyramidal neurones elicited by NMDA and QUIN are Ca2+ dependent while the actions of QUIS are not.

2-Amino-5-phosphonovalerate↗
PubMed1985

Effects of intracerebral injections of quinolinic acid on serotonergic neurons in the rat brain.

The effects of intrastriatal and intrahippocampal injections of the excitotoxic amino acid, quinolinic acid (QUIN), were examined in the rat using immunohistochemical and neurochemical techniques. Serotonin and 5-hydroxyindoleacetic acid measurements at 90 min, 6 h, 4 and 11 days following QUIN administration revealed highly elevated levels of the metabolite in the injected nuclei, with peak increases occurring after 4 days. Serotonin levels remained largely unchanged over the same time period. Direct visualization of hippocampal serotonergic fibers by immunohistochemistry demonstrated morphological changes (varicosities, swellings) in otherwise undamaged serotonin-positive afferents 4 days following a local QUIN injection. Hippocampal serotonin turnover was assessed at 4 days after an intrahippocampal QUIN-application: following inhibition of aromatic amino acid decarboxylase, the accumulation of 5-hydroxytryptophan was twice as rapid in QUIN-lesioned hippocampi as in controls. Dose-response relationships, examination of brain regions distant from the two injection sites and the temporal sequence of the changes described here suggest a close association between QUIN-induced neuronal degeneration and alterations in the serotonergic system.

Animals↗
PubMed1989

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.

Animals↗