Melatonin plays a protective role in quinolinic acid-induced neurotoxicity in the rat hippocampus

The neuroprotective effect of melatonin against the quinolinic acid-induced degeneration of rat hippocampal neurons was investigated. Three groups of rats were given intrahippocampal injections of either; saline, quinolinic acid or i.p. injections of melatonin prior to and after being injected with quinolinic acid. On the fifth day after the intrahippocampal injections the brains were removed and the hippocampi either sectioned and stained for microscopic examination or used in glutamate receptor binding studies. The results show that melatonin protects hippocampal neurons from quinolinic acid-induced neurodegeneration and partially prevents the decrease in glutamate receptor numbers caused by quinolinic acid. Thus, melatonin has the potential to reduce hippocampal neuronal damage induced by neurotoxins such as quinolinic acid.     

Kynurenic acid antagonizes hippocampal quinolinic acid neurotoxicity: behavioral and histological evaluation

In the present study, we evaluate the ability of kynurenic acid to protect hippocampal neurons from the neurotoxicity of the N-methyl-D-aspartate (NMDA) agonist quinolinic acid. Bilateral intrahippocampal injection of quinolinic acid (120 nmol) led to severe behavioral disturbances and total loss of hippocampal neurons. Intrahippocampal co-injection of kynurenic acid (360 nmol) completely prevented cell loss and behavioral disturbances. However, the protection was incomplete when kynurenic acid was intraperitoneally injected (500 mg/kg, repeated during 4 days). These above results indicate that kynurenic acid can antagonize the neuronal degeneration mediated by excessive stimulation of NMDA receptors in vivo.     

Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis

Kynurenine 3-mono-oxygenase, one of the key enzymes of the "kynurenine pathway", catalyses the formation of 3-hydroxykynurenine and may direct the neo-synthesis of quinolinic and kynurenic acids. While 3-hydroxykynurenine and quinolinic acid have neurotoxic properties, kynurenic acid antagonizes excitotoxic neuronal death. Here we report that the expression and activity of kynurenine 3-mono-oxygenase significantly increased in the spinal cord of rats with experimental allergic encephalopathy, an experimental model of multiple sclerosis. As a consequence of this increase, the spinal cord content of 3-hydroxykynurenine and quinolinic acid reached neurotoxic levels. We also report that systemic administration of Ro 61-8048, a selective kynurenine 3-mono-oxygenase inhibitor, reduced the increase of both 3-hydroxykynurenine and quinolinic acid, and caused accumulation of kynurenic acid. In the brain and spinal cord of the controls, kynurenine 3-mono-oxygenase immunoreactivity was located in granules (probably mitochondria) present in the cytoplasm of both neurons and astroglial cells. In the spinal cord of rats with experimental allergic encephalopathy, however, cells with a very intense kynurenine 3-mono-oxygenase immunoreactivity, also able to express class II major histocompatibility complex and inducible nitric oxide synthase, were found in perivascular, subependymal and subpial locations. These cells (most probably macrophages) were responsible for the large increase in 3-hydroxykynurenine and quinolinic acid found in the spinal cords of affected animals. The results show that cells of the immune system are responsible for the increased formation of 3-hydroxykynurenine and quinolinic acid, two neurotoxic metabolites that accumulate in the central nervous system of rats with experimental allergic encephalomyelitis. They also demonstrate that selective kynurenine 3-mono-oxygenase inhibitors reduce the neo-synthesis of these toxins.     

Excitotoxic brain damage involves early peroxynitrite formation in a model of Huntington's disease in rats: protective role of iron porphyrinate 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III)

Oxidative/nitrosative stress is involved in NMDA receptor-mediated excitotoxic brain damage produced by the glutamate analog quinolinic acid. The purpose of this work was to study a possible role of peroxynitrite, a reactive oxygen/nitrogen species, in the course of excitotoxic events evoked by quinolinic acid in the brain. The effects of Fe(TPPS) (5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III)), an iron porphyrinate and putative peroxynitrite decomposition catalyst, were tested on lipid peroxidation and mitochondrial function in brain synaptic vesicles exposed to quinolinic acid, as well as on peroxynitrite formation, nitric oxide synthase and superoxide dismutase activities, lipid peroxidation, caspase-3-like activation, DNA fragmentation, and GABA levels in striatal tissue from rats lesioned by quinolinic acid. Circling behavior was also evaluated. Increasing concentrations of Fe(TPPS) reduced lipid peroxidation and mitochondrial dysfunction induced by quinolinic acid (100 microM) in synaptic vesicles in a concentration-dependent manner (10-800 microM). In addition, Fe(TPPS) (10 mg/kg, i.p.) administered 2 h before the striatal lesions, prevented the formation of peroxynitrite, the increased nitric oxide synthase activity, the decreased superoxide dismutase activity and the increased lipid peroxidation induced by quinolinic acid (240 nmol/microl) 120 min after the toxin infusion. Enhanced caspase-3-like activity and DNA fragmentation were also reduced by the porphyrinate 24 h after the injection of the excitotoxin. Circling behavior from quinolinic acid-treated rats was abolished by Fe(TPPS) six days after quinolinic acid injection, while the striatal levels of GABA, measured one day later, were partially recovered. The protective effects that Fe(TPPS) exerted on quinolinic acid-induced lipid peroxidation and mitochondrial dysfunction in synaptic vesicles suggest a primary action of the porphyrinate as an antioxidant molecule. In vivo findings suggest that the early production of peroxynitrite, altogether with the enhanced risk of superoxide anion (O2*-) and nitric oxide formation (its precursors) induced by quinolinic acid in the striatum, are attenuated by Fe(TPPS) through a recovery in the basal activities of nitric oxide synthase and superoxide dismutase. The porphyrinate-mediated reduction in DNA fragmentation simultaneous to the decrease in caspase-3-like activation from quinolinic acid-lesioned rats suggests a prevention in the risk of peroxynitrite-mediated apoptotic events during the course of excitotoxic damage in the striatum. In summary, the protective effects that Fe(TPPS) exhibited both under in vitro and in vivo conditions support an active role of peroxynitrite and its precursors in the pattern of brain damage elicited by excitotoxic events in the experimental model of Huntington's disease. The neuroprotective mechanisms of Fe(TPPS) are discussed.     

Prolonged infusion of quinolinic acid into rat striatum as an excitotoxic model of neurodegenerative disease

The neurotoxic effects of prolonged exposure of rat striatum to quinolinic acid in vivo was evaluated through assays of neurochemical markers for major neuronal populations. Continuous intrastriatal quinolinic acid infusion for 14 days produced a dose-dependent depletion of striatal choline acetyltransferase (ChAT) activity, glutamic acid decarboxylase (GAD) activity, and somatostatin content. ChAT activity was significantly reduced by quinolinic acid at doses of 90, 270, and 540 nmol/day, while GAD activity and somatostatin content were decreased only at doses of 270 and 540 nmol/day. NADPH-diaphorase histochemistry revealed a loss of striatal NADPH-diaphorase neurons as a result of quinolinic acid infusion at a dose of 270 nmol/day. The neurotoxic lesion induced by prolonged quinolinic acid exposure in vivo can be used as a potential model for studying excitotoxic mechanisms in neurodegenerative disease.     

Prevention of quinolinic acid neurotoxicity in rat hippocampus in vitro by zinc. Ultrastructural observations

The effect of zinc on the development and evolution of quinolinic acid-induced alterations in the rat hippocampus in culture was studied ultrastructurally. Zinc, although it possesses intrinsic cytotoxic properties, after application in concentrations comparable with those encountered in vivo, was able to prevent typically observed responses after quinolinic acid exposure, either early or late damage to hippocampal neurons. The results further support the concept of a potential protective effect of zinc against the neurotoxicity of particular excitotoxins.     

Poly(ADP-ribose) polymerase-1 is involved in the neuronal death induced by quinolinic acid in rats

Reactive oxygen and nitrogen species formation leads to DNA damage in animals treated with quinolinic acid. Poly(ADP-ribose) polymerase-1 (PARP-1) is a protein involved in the DNA base excision repair system. Its overactivation promotes cellular energy deficit and necrosis. Here, we evaluated the effect of PJ-34, a potent inhibitor of PARP-1, on the neuronal damage induced by quinolinic acid. Animals were administered with PJ-34 (10 mg/kg, i.p.), 1 h before and 1 h after a striatal infusion of 1 μl of quinolinic acid (240 nmol). PJ-34 clearly attenuated the circling behavior produced by quinolinic acid and completely prevented the histological damage induced by the toxin. The protective effect of PJ-34 suggests that PARP-1 activation is playing an active role in the neuronal death induced by quinolinic acid.     

Chemical and anatomical changes in the striatum and substantia nigra following quinolinic acid lesions in the striatum of the rat: a detailed time course of the cellular and GABA(A) receptor changes

The pattern and time-course of cellular, neurochemical and receptor changes in the striatum and substantia nigra were investigated following unilateral quinolinic acid lesions of the striatum in rats. The results showed that in the central region of the striatal lesion there was a major loss of Nissl staining of the small to medium sized cells within 2 h and a substantial loss of neuronal staining within 24 h after lesioning. Immunohistochemical studies showed a total loss of calbindin immunoreactivity, a known marker of GABAergic striatal projection neurons, throughout the full extent of the quinolinic acid lesion within 24 h. Similarly, within 24 h, there was a total loss of somatostatin/neuropeptide Y cells in the centre of the lesion but in the periphery of the lesion these cells remained unaltered at all survival times. Striatal GABA(A) receptors remained unchanged in the lesion for 7 days, and then declined in density over the remainder of the time course. Glial fibrillary acidic protein immunoreactive astrocytes were present in the periphery of the lesion at 7 days, occupied the full extent of the lesion by 4 weeks, and remained elevated for up to 2 months. In the substantia nigra, following placement of a striatal quinolinic acid lesion, there was: a loss of substance P immunoreactivity within 24 h; a marked astrocytosis evident from 1-4 weeks postlesion; and, a major increase in GABA(A) receptors in the substantia nigra which occurred within 2 h postlesion and was sustained for the remainder of the time course (15 months). This study shows that following quinolinic acid lesions of the striatum there is a major loss of calbindin and somatostatin/neuropeptide Y immunoreactive cells in the striatum within 24 h, and a marked increase in GABA(A) receptors in the substantia nigra within 2 h. These findings are similar to the changes in the basal ganglia in Huntington's disease and provide further evidence supporting the use of the quinolinic acid lesioned rat as an animal model of Huntington's disease.     

Quinolinic acid neurotoxicity in the nucleus basalis antagonized by kynurenic acid

Quinolinic acid, a metabolite of tryptophan, behaves as an excitotoxic amino acid. It has been proposed that quinolinic acid might be implicated in neurodegenerative diseases. The related metabolite, kynurenic acid, has been found to be a powerful antagonist of quinolinic acid. The ability of quinolinic acid, alone or in combination with kynurenic acid, to destroy cholinergic neurons projecting to the cortex was examined by morphological and biochemical criteria. The compounds were injected unilaterally into the nbm of the rat. Neuronal destruction of the basal forebrain occurred with quinolinic acid alone; however, no cell loss was observed when kynurenic and quinolinic acid were co-injected. Quinolinic acid lesions of the nucleus basalis caused significant decreases in cortical choline acetyltransferase, acetylcholinesterase, high affinity choline uptake and ³H-acetylcholine release. These reductions in cortical cholinergic markers were prevented by coinjecting kynurenic with quinolinic acid. A significant decrease in cortical choline acetyltransferase activity was observed three months following quinolinic acid lesions of the nucleus basalis. The results indicate that quinolinic acid can be used as an endogenous neurotoxin to produce lesions of the nbm resulting in impaired cortical cholinergic function similar to that seen in Alzheimer's disease.     

Localization of quinolinic acid metabolizing enzymes in the rat brain. Immunohistochemical studies using antibodies to 3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase

Specific antibodies raised in rabbits against 3-hydroxyanthranilic acid oxygenase (EC 1.13.11.6) and quinolinic acid phosphoribosyltransferase (EC 1.13.11.6) and quinolinic acid phosphoribosyltransferase (EC 2.4.2.19) were used in immunohistochemical studies to map the cellular localization of the quinolinic acid metabolizing enzymes in the adult male rat brain. 3-Hydroxyanthranilic acid oxygenase immunoreactivity was found to be present in glial cells of presumed astroglial identity, as judged by co-localization with glial fibrillary acidic protein. 3-Hydroxyanthranilic acid oxygenase-immunoreactive glial cells were present in all brain regions and within major fiber tracts. The density of 3-hydroxyanthranilic acid oxygenase-immunoreactive glial cells as well as the intensity of staining of these cells differed among brain regions. In general, telencephalic acid diencephalic areas harbored a larger number of 3-hydroxyanthranilic acid oxygenase-positive cells than did mesencephalic regions. In the former regions the caudate nucleus, septum, nucleus accumbens, neocortex and hippocampus were particularly enriched in 3-hydroxyanthranilic acid oxygenase-immunoreactive cells. In the thalamus, regional differences were noted with regard to the intensity of staining among glial cells with high densities of 3-hydroxyanthranilic acid oxygenase cells in the anteroventral, reticular and ventromedial nuclei. In the inferior and superior colliculi, numerous 3-hydroxyanthranilic acid oxygenase-positive glial cells were found in all layers. In the hypothalamus, 3-hydroxyanthranilic acid oxygenase-immunoreactive glial cells were encountered in the zona incerta, the lateral hypothalamic area, the caudal preoptic region and in the dorsomedial nucleus. In the mesencephalon, the substantia nigra contained numerous, moderately stained cells. At caudal levels of the brain-stem, a relatively large number of cells was detected in the nucleus of the solitary tract, the pontine nucleus and in the fascial nerve nucleus, while other nuclei, such as the reticular formation and the area postrema were relatively poor in 3-hydroxyanthranilic acid oxygenase-immunoreactive cells. In addition to staining of glial cells, neuronal cell bodies containing 3-hydroxyanthranilic acid oxygenase immunoreactivity were detected in the main and in the accessory olfactory bulb, as well as in the ventromedial nucleus of the hypothalamus. Quinolinic acid phosphoribosyltransferase immunoreactivity was observed within glial cells and in association with neuronal cell bodies. Some, but not all, quinolinic acid phosphoribosyltransferase positive glial cells contained glial fibrillary acidic protein (K?hl     

Quinolinic acid neurotoxicity in the nucleus basalis antagonized by kynurenic acid

Quinolinic acid, a metabolite of tryptophan, behaves as an excitotoxic amino acid. It has been proposed that quinolinic acid might be implicated in neurodegenerative diseases. The related metabolite, kynurenic acid, has been found to be a powerful antagonist of quinolinic acid. The ability of quinolinic acid, alone or in combination with kynurenic acid, to destroy cholinergic neurons projecting to the cortex was examined by morphological and biochemical criteria. The compounds were injected unilaterally into the nbm of the rat. Neuronal destruction of the basal forebrain occurred with quinolinic acid alone; however, no cell loss was observed when kynurenic and quinolinic acid were co-injected. Quinolinic acid lesions of the nucleus basalis caused significant decreases in cortical choline acetyltransferase, acetylcholinesterase, high affinity choline uptake and ³H-acetylcholine release. These reductions in cortical cholinergic markers were prevented by coinjecting kynurenic with quinolinic acid. A significant decrease in cortical choline acetyltransferase activity was observed three months following quinolinic acid lesions of the nucleus basalis. The results indicate that quinolinic acid can be used as an endogenous neurotoxin to produce lesions of the nbm resulting in impaired cortical cholinergic function similar to that seen in Alzheimer's disease.     

Chemical and anatomical changes in the striatum and substantia nigra following quinolinic acid lesions in the striatum of the rat: a detailed time course of the cellular and GABAA receptor changes

The pattern and time-course of cellular, neurochemical and receptor changes in the striatum and substantia nigra were investigated following unilateral quinolinic acid lesions of the striatum in rats. The results showed that in the central region of the striatal lesion there was a major loss of Nissl staining of the small to medium sized cells within 2 h and a substantial loss of neuronal staining within 24 h after lesioning. Immunohistochemical studies showed a total loss of calbindin immunoreactivity, a known marker of GABAergic striatal projection neurons, throughout the full extent of the quinolinic acid lesion within 24 h. Similarly, within 24 h, there was a total loss of somatostatin/neuropeptide Y cells in the centre of the lesion but in the periphery of the lesion these cells remained unaltered at all survival times. Striatal GABA_A receptors remained unchanged in the lesion for 7 days, and then declined in density over the remainder of the time course. Glial fibrillary acidic protein immunoreactive astrocytes were present in the periphery of the lesion at 7 days, occupied the full extent of the lesion by 4 weeks, and remained elevated for up to 2 months. In the substantia nigra, following placement of a striatal quinolinic acid lesion, there was: a loss of substance P immunoreactivity within 24 h; a marked astrocytosis evident from 1–4 weeks postlesion; and, a major increase in GABA_A receptors in the substantia nigra which occurred within 2 h postlesion and was sustained for the remainder of the time course (15 months). This study shows that following quinolinic acid lesions of the striatum there is a major loss of calbindin and somatostatin/neuropeptide Y immunoreactive cells in the striatum within 24 h, and a marked increase in GABA_A receptors in the substantia nigra within 2 h. These findings are similar to the changes in the basal ganglia in Huntington's disease and provide further evidence supporting the use of the quinolinic acid lesioned rat as an animal model of Huntington's disease.     

Neurotoxicity induced by continuous infusion of quinolinic acid into the lateral ventricle in rats

Acute intrastriatal injection of quinolinic acid (QA) caused a significant reduction of choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activities as well as a decrease of the specific binding of [3H]hemicholinium-3. Pretreatment with MK-801 completely blocked the QA-induced neurotoxicity. Continuous infusion of QA into the lateral ventricle resulted in a reduction of hippocampal and cortical ChAT activities while GAD activities were unchanged. These results suggest that continuous infusion of QA into the lateral ventricle could be a useful technique for the study of chronic neurodegenerative diseases including Alzheimer's disease.     

Loss of the acoustic startle response following neurotoxic lesions of the caudal pontine reticular formation: possible role of giant neurons.

The effect of the excitotoxic N-methyl-D-aspartate agonist quinolinic acid in the caudal pontine reticular formation on the acoustic startle response was investigated in rats. Bilateral injections of 90 nmol of quinolinic acid led to large lesions in the reticular formation characterized by the loss of all neurons and a marked reduction or even abolition of the acoustic startle response; 18 nmol of quinolinic acid led to smaller lesions characterized by a selective loss of giant neurons within the caudal pontine reticular formation and a reduction of the startle amplitude. The partial correlation analysis revealed that the reduction of the amplitude of the acoustic startle response can be correlated with the loss of the giant neurons (r = 0.575; d.f. = 29; P less than 0.001) but not with the reduction of the number of all neurons (r = 0.207; d.f. = 29; P greater than 0.2) in the caudal pontine reticular formation. These findings were reconciled with electrophysiological and anatomical data indicating that the giant neurons in the caudal pontine reticular formation receive acoustic input and project to motoneurons of the spinal cord. It is concluded that the caudal pontine reticular formation is an important element of the startle pathway and that the giant reticulospinal neurons constitute an important part of the sensorimotor interface mediating this response.     

Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues.

Experiment 1 investigated the effects of catecholaminergic deafferentation or cell body lesions of the amygdala on fear conditioning to explicit and contextual cues. Bilateral infusions of quinolinic acid mainly damaged neurons within the basolateral region of the amygdala. 6-Hydroxydopamine infusions at the same coordinates resulted in an 86% depletion of noradrenaline and a 63% depletion of dopamine from the amygdala, but had no effect on the concentration of 5-hydroxytryptamine. After recovery from surgery, lesioned rats and controls were exposed to pairings of an auditory (clicker) conditioned stimulus and (foot shock) unconditioned stimulus in a distinctive environment. During testing, rats with both 6-hydroxydopamine and cell body lesions showed severely impaired conditioning to explicit cues, compared with controls, indicated by their reduced suppression of drinking when the conditioned stimulus was introduced into a separate, lick-operant chamber. Neither lesion affected fear conditioning to contextual cues, measured as preference for a "safe" environment over the one in which they were shocked. In Experiment 2, rats received bilateral, ibotenic acid-induced lesions of the hippocampal formation. Lesioned rats and controls were again tested for aversive conditioning to explicit and contextual cues. Rats with cell body lesions of the hippocampus showed normal suppression of drinking in the presence of the conditioned stimulus, but were severely impaired in choosing the safe environment based on contextual cues alone. These results suggest a double dissociation of the effects of amygdala and hippocampal damage on fear conditioning to explicit and contextual cues.     

Lithium suppresses excitotoxicity-induced striatal lesions in a rat model of Huntington's disease

Huntington's disease is a progressive, inherited neurodegenerative disorder characterized by the loss of subsets of neurons primarily in the striatum. In this study, we assessed the neuroprotective effect of lithium against striatal lesion formation in a rat model of Huntington's disease in which quinolinic acid was unilaterally infused into the striatum. For this purpose, we used a dopamine receptor autoradiography and glutamic acid decarboxylase mRNA in situ hybridization analysis, methods previously shown to be adequate for quantitative analysis of the excitotoxin-induced striatal lesion size.Here we demonstrated that subcutaneous injections of LiCl for 16 days prior to quinolinic acid infusion considerably reduced the size of quinolinic acid-induced striatal lesion. Furthermore, these lithium pre-treatments also decreased the number of striatal neurons labeled with the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. Immunohistochemistry and western blotting demonstrated that lithium-elicited neuroprotection was associated with an increase in Bcl-2 protein levels.Our results raise the possibility that lithium may be considered as a neuroprotective agent in treatment of neurodegenerative diseases such as Huntington's disease.     

Immunohistochemical localization of quinolinic acid phosphoribosyltransferase in the human neostriatum.

The localization and distribution of quinolinic acid phosphoribosyltransferase, the degradative enzyme of the endogenous excitotoxin quinolinic acid, were studied in the post mortem human neostriatum by immunohistochemistry. In eight neurologically normal human brains, quinolinic acid phosphoribosyltransferase immunoreactivity was detected in both glial cells and neurons. Typically, glial cells containing quinolinic acid phosphoribosyltransferase immunoreactivity had numerous processes radiating from the cell bodies. In Nissl-counterstained sections, most quinolinic acid phosphoribosyltransferase-immunoreactive glial cells showed round, large and pale nuclei. These morphological features indicate that they are probably astrocytes. Neurons containing quinolinic acid phosphoribosyltransferase immunoreactivity had different sizes and shapes and were tentatively classified into three subpopulations. Most were medium-sized cells with ovoid or elongated perikarya. Small quinolinic acid phosphoribosyltransferase-immunoreactive neurons, often spheroid in shape, were particularly noted in a zone of the caudate nucleus adjacent to the lateral ventricle. A few large quinolinic acid phosphoribosyltransferase-positive neurons were also present in both the caudate and putamen. The somatic and dendritic morphology of quinolinic acid phosphoribosyltransferase-immunoreactive neurons closely resembles that of aspiny neurons seen in Golgi preparations. The localization of the specific quinolinic acid-catabolizing enzyme in distinct populations of neostriatal cells suggests specific functional correlates. It remains to be examined how the anatomical organization of quinolinic acid phosphoribosyltransferase immunoreactivity relates to the degradation of quinolinic acid in the striatum, and if the morphological characteristics and distribution of quinolinic acid phosphoribosyltransferase-immunoreactive cells are of relevance for the pathogenesis of neurodegenerative basal ganglia disorders.     

Quinolinic acid: effects on brain catecholamine and c-AMP content during L-dopa and reserpine administration.

The catecholamine content in rat brain tissue was determined following the administration of quinolinic acid alone or combined either with L-dopa and decarboxylase inhibitor or reserpine. Quinolinic acid alone decreased the levels of dopamine and noradrenaline, as well as those of c-AMP, and increased those of adrenaline. Treatment with L-dopa/decarboxylase inhibitor reversed the suppressing effect of quinolinic acid on dopamine, but not on noradrenaline. Reserpine alone depleted the contents of dopamine, noradrenaline and adrenaline. It could be concluded from the effects of quinolinic acid and reserpine given together that quinolinic acid suppresses the depletion of amines induced by reserpine. It has been demonstrated that quinolinic acid leads to injuries of nerve-cell bodies in pars compacta of the substantia nigra and in the striatum. Quinolinic acid is a natural metabolite of tryptophan, normally occurring in the liver, kidney and brain (Wolfensberger et al. 1983; Moroni et al. 1984). This compound exhibits convulsant and neuron excitant properties (Stone et al. 1987). It induces a selective pattern of neuronal degeneration both at the site of intracerebral injection (Schwarcz et al. 1983; Stone et al. 1987) and after general (intracardiac) administration (Beskid and Markiewicz 1988). The ability of quinolinic acid to produce neurotoxicity was greater in the striatum than in other parts of the brain. This prompted us to study catecholamine and c-AMP levels in rat brain tissue following quinolinic acid and L-dopa administration, as well as the influence of reserpine on quinolinic acid action.     

Effects of MK-801, ketamine and alaptide on quinolinate models in the maturing hippocampus.

The ability of the N-methyl-D-aspartate receptor antagonists, MK-801, ketamine and alaptide [a newly synthesized cyclo(1-amino-1-cyclopentane-carbonyl-L-alanyl) with protective properties in models of hypoxia], to prevent neuronal degeneration caused by intracerebroventricular application of quinolinic acid was investigated. Neurodegenerative effects of quinolinate in the hippocampal formation were found to increase with the degree of maturity of glutamatergic target structures. A protective potency of the N-methyl-D-aspartate receptor antagonists was observed at all developmental stages studied (12- and 30-day-old and adult rats). MK-801 showed the highest efficacy, alaptide the lowest. These findings suggest a parallelism in maturity of glutamatergic transmission processes as one prerequisite of quinolinate vulnerability and postnatal increases of target fields of the protectives. Application of MK-801 or ketamine after quinolinate injection intensified their protective effects when compared to simultaneous or preadministration. This observation is interpreted as indicating that quinolinate is a prompter of a delayed neurodegenerative process rather than acting immediately as a toxicant.     

Immunohistochemical identification of quinolinic acid phosphoribosyltransferase in glial cultures from rat brain

Glial cell cultures were shown to contain 3 identifiable classes of cells which could be specifically stained with antibodies directed against quinolinic acid phosphoribosyltransferase (QPRT), the catabolic enzyme of the endogenous excitotoxin quinolinic acid. Some, but not all, QPRT-positive cells also contained glial fibrillary acidic protein. These cultures may constitute an in vitro system in which cerebral quinolinic acid metabolism and function can be examined.