Intrastriatal Administration Of Quinolinic Acid Research Articles

Exploring the neuroprotective effects of montelukast on brain inflammation and metabolism in a rat model of quinolinic acid-induced striatal neurotoxicity

BackgroundOne intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington’s disease. Our aim is to evaluate the effects of the cysteinyl leukotriene receptor antagonist montelukast (MLK), which exhibited neuroprotection in different preclinical models of neurodegeneration, on QA-induced neuroinflammation and regional metabolic functions.MethodsThe right and left striatum of Sprague Dawley and athymic nude rats were injected with QA and vehicle (VEH), respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or VEH for 14 days. At 14 and 30 days post-lesion, animals were monitored with magnetic resonance imaging (MRI) and positron emission tomography (PET) using [18F]-VC701, a translocator protein (TSPO)-specific radiotracer. Striatal neuroinflammatory response was measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent a [18F]-FDG PET study at baseline and 4 months after lesion. [18F]-FDG PET data were then used to assess metabolic connectivity between brain regions by applying a covariance analysis method.ResultsMLK treatment was not able to reduce the QA-induced increase in striatal TSPO PET signal and MRI lesion volume, where we only detected a trend towards reduction in animals treated with 10 mg/kg of MLK. Post-mortem immunofluorescence analysis revealed that MLK attenuated the increase in striatal markers of astrogliosis and activated microglia in the lesioned hemisphere. We also found a significant increase in a marker of anti-inflammatory activity (MannR) and a trend towards reduction in a marker of pro-inflammatory activity (iNOS) in the lesioned striatum of MLK—compared to VEH-treated rats. [18F]-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of VEH-treated rats at 4 months after lesion. MLK administration preserved glucose metabolism in these cortical regions, but not in the striatum. Finally, MLK was able to counteract changes in metabolic connectivity and measures of network topology induced by QA, in both lesioned and non-lesioned hemispheres.ConclusionsOverall, MLK treatment produced a significant neuroprotective effect by reducing neuroinflammation assessed by immunofluorescence and preserving regional brain metabolism and metabolic connectivity from QA-induced neurotoxicity in cortical and subcortical regions.

Induction of Neuroinflammatory Response and Histopathological Alterations Caused by Quinolinic Acid Administration in the Striatum of Glutaryl-CoA Dehydrogenase Deficient Mice.

Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase (GCDH) activity. Patients usually present progressive cortical leukodystrophy and commonly develop acute bilateral striatal degeneration mainly during infections that markedly worse their prognosis. A role for quinolinic acid (QA), a key metabolite of the kynurenine pathway, which is activated during inflammatory processes, on the pathogenesis of the acute striatum degeneration occurring in GA I was proposed but so far has not yet been evaluated. Therefore, we investigated whether an acute intrastriatal administration of quinolinic acid (QA) could induce histopathological alterations in the striatum of 30-day-old wild-type (WT) and GCDH knockout (Gcdh-/-) mice. Striatum morphology was evaluated by hematoxylin and eosin, T lymphocyte presence (CD3), and glial activation (GFAP and S100β) by immunohistochemistry and 3-nitrotyrosine (YNO2) by immunofluorescence. QA provoked extensive vacuolation, edema, and especially lymphocyte infiltration in the striatum of Gcdh-/-. QA also enhanced CD3 staining and the number of YNO2 positive cells in Gcdh-/- mice, relatively to WT, indicating T lymphocyte infiltration and nitrosative stress, respectively. QA-treated WT mice also showed an increase of GFAP and S100β staining, which is indicative of reactive astrogliosis, whereas the levels of these astrocytic proteins were not changed in Gcdh-/- QA-injected mice. The present data indicate that QA significantly contributes to the histopathological changes observed in the striatum of Gcdh-/- mice.

Absence of aryl hydrocarbon receptors increases endogenous kynurenic acid levels and protects mouse brain against excitotoxic insult and oxidative stress.

L-kynurenine (Kyn) is a key element of tryptophan metabolism; it is enzymatically converted by kynurenine aminotransferase II (KAT II) to kynurenic acid (KYNA), which acts as an antagonist to the NMDA receptor-glycine site. Kyn is also an endogenous ligand of the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of a diverse set of genes. KYNA levels are reduced in several regions of the brain of Huntington's disease (HD) patients. The present work uses an AhR-null mouse and age-matched wild-type mice to determine the effect of the absence of AhR on KYNA availability. We found that, in AhR-null mice, there is an increase of KYNA levels in specific brain areas associated with higher expression of KAT II. Moreover, we induced an excitotoxic insult by intrastriatal administration of quinolinic acid, a biochemical model of HD, in both AhR-null and wild-type mice to evaluate the neurological damage as well as the oxidative stress caused by the lesion. The present work demonstrates that, in specific brain regions of AhR-null mice, the levels of KYNA are increased and that this induces a neuroprotective effect against neurotoxic insults. Moreover, AhR-null mice also show improved motor performance in the rotarod test, indicating a constitutive protection of striatal tissue.

Targeting Neuro-Inflammatory Cytokines and Oxidative Stress by Minocycline Attenuates Quinolinic-Acid-Induced Huntington’s Disease-Like Symptoms in Rats

Recent experimental and clinical reports support the fact that the minocycline exhibits significant neuroprotective activity in neurodegenerative diseases. However, its mechanism of neuroprotection is still far from our understanding. Besides, minocycline does not always produce neuroprotective effect. Therefore, this study has been designed to explore the possible mechanism of minocycline in experimental model of HD in rats. Intrastriatal administration of quinolinic acid caused a significant reduction in body weight, motor dysfunction (impaired locomotor activity, rotarod performance, and beam walk test), oxidative damage (as evidenced by increase in lipid peroxidation, nitrite concentration, and depletion of super oxide dismutase and catalase), increased TNF-α and IL-6 levels as compared to the sham-treated animals. Minocycline (25, 50, and 100mg/kg) treatment (for 21days) significantly improved body weight, locomotor activity, rotarod performance, balance beam walk performance, oxidative defense, attenuated TNF-α and IL-6 levels as compared to quinolinic-acid (QA)-treated animals. This study provides evidence that minocycline might have neuroprotective effect against QA-induced Huntington-like behavioral, biochemical alterations, and neuroinflammation in rats.

Licofelone attenuates quinolinic acid induced Huntington like symptoms: Possible behavioral, biochemical and cellular alterations

Cyclo-oxygenase and lipoxygenase enzymes are involved in arachidonic acid metabolism. Emerging evidence indicates that cyclo-oxygenase and lipoxygenase inhibitors prevent neurodegenerative processes and related complications. Therefore, the present study has been designed to explore the neuroprotective potential of licofelone (dual COX-2/5-LOX inhibitor) against quinolinic acid induced Huntington like symptom in rats. Intrastriatal administration of quinolinic acid significantly caused reduction in body weight and motor function (locomotor activity, rotarod performance and beam walk test), oxidative defense (as evidenced by increased lipid peroxidation, nitrite concentration and decreased endogenous antioxidant enzymes), alteration in mitochondrial enzyme complex (I, II and IV) activities, raised TNF-α level and striatal lesion volume as compared to sham treated animals. Licofelone (2.5, 5 and 10 mg/kg) treatment significantly improved body weight, locomotor activity, rotarod performance, balance beam walk performance, oxidative defense, mitochondrial enzyme complex activities and attenuated TNF-α level and striatal lesion as compared to control (quinolinic acid). The present study highlights that licofelone attenuates behavioral, biochemical and cellular alterations against quinolinic acid induced neurotoxicity and this could be an important therapeutic avenue to ameliorate the Huntington like symptoms.

Acute intrastriatal administration of quinolinic acid provokes hyperphosphorylation of cytoskeletal intermediate filament proteins in astrocytes and neurons of rats

In the present study we investigated the effect of in vivo intrastriatal injection of quinolinic acid (QA) on cytoskeletal proteins in astrocytes and neurons of young rats at early stage (30 min) after infusion. QA (150nmoles/0.5 µL) significantly increased the in vitro phosphorylation of the low molecular weight neurofilament subunit (NFL) and the glial fibrillary acidic protein (GFAP) of neurons and astrocytes, respectively. This effect was mediated by cAMP-dependent protein kinase A (PKA), protein kinase C (PKC) and Ca 2+/calmodulin-dependent protein kinase II (PKCaMII). In contrast, mitogen activated protein kinases were not activated by QA infusion. Furthermore, the specific N-methyl-D-aspartate (NMDA) antagonist MK-801 (0.25 mg/kg i.p), the antioxidant L-NAME (60 mg\\kg\\day), and diphenyldisselenide (PheSe) 2 (0.625 mg\\kg\\day) injected prior to QA infusion totally prevented QA-induced cytoskeletal hyperphosphorylation. We also observed that QA-induced hyperphosphorylation was targeted at the Ser55 phosphorylating site on NFL head domain, described as a regulatory site for NF assembly in vivo. This effect was fully prevented by MK801, by the PKA inhibitor H89 and by (PheSe) 2, whereas staurosporine (PKC inhibitor) only partially prevented Ser55 phosphorylation. The PKCaMII inhibitor (KN93) and the antioxidant L-NAME failed to prevent the hyperphosphorylation of Ser55 by QA infusion. Therefore, we presume that QA-elicited hyperphosphorylation of the neural cytoskeleton, and specially of NFLSer55, achieved by intrastriatal QA injection could represent an early step in the pathophysiological cascade of deleterious events exerted by QA in rat striatum. Our observations also indicate that NMDA-mediated Ca 2+ events and oxidative stress may be related to the altered protein cytoskeleton hyperphosphorylation observed with important implications for brain function.

Protective effect of rofecoxib and nimesulide against intra-striatal quinolinic acid-induced behavioral, oxidative stress and mitochondrial dysfunctions in rats

Role of cyclooxygenase (COX) enzyme has been well documented in both physiological and pathological conditions. COX-1 and COX-2 converts arachidonic acid into prostaglandins. Non-selective inhibition of COXs produces undesirable effects, whereas selective COX-2 inhibition produces protective effects in various inflammatory diseases. Recently, cyclooxygenase (COX) inhibitors have been implicated as a neuroprotectant in the treatment of various neurodegenerative diseases. Quinolinic acid is an endogenous excitotoxin that causes neurotoxicity in diverse areas of the brain and produces motor dysfunction. Present study is an attempt to investigate the possible role of COX inhibitors (selective COX-2 inhibitor and preferential COX-2 inhibitors) against quinolinic acid-induced behavioral, oxidative stress and mitochondrial enzyme complex alterations in rats. Intra-striatal administration of quinolinic acid (300 nmol) caused significant reduction in body weight (9%), motor in-coordination, oxidative damage [increased MDA (100%), nitrite concentration (195%), depleted SOD (71%), catalase levels (70%)] and alteration in mitochondrial enzyme complex activity (decreased complex I (50%), II (50%) and IV(62%)) as compared to sham operated animals. Chronic treatment with rofecoxib (10 and 20 mg/kg, p.o.) and nimesulide (10 and 20 mg/kg, p.o.) significantly attenuated quinolinic acid-induced behavioral and biochemical alterations as compared to quinolinic acid 300 nmol treated group. Further, rofecoxib (10, 20 mg/kg) and nimesulide (20 mg/kg) significantly restored mitochondrial enzyme complex activities in striatum as compared to quinolinic acid 300 nmol treated group. Present study highlights the therapeutic potential of cyclooxygenase inhibitors against quinolinic acid induced neurotoxicity.

Spermine improves recognition memory deficit in a rodent model of Huntington’s disease

Huntington’s disease (HD) is a progressive neurodegenerative disorder associated with motor and cognitive impairment. Intrastriatal administration of quinolinic acid (QA) causes neurodegeneration, glial proliferation and cognitive impairment in animals, which are similar to these seen in human HD. Since polyamines improve memory in cognitive tasks, we now tested if the post-training intrastriatal administration of spermine, an agonist of the polyamine site at the NMDA receptor, reverses the deficits in the object recognition task induced by QA. Bilateral striatal injections of QA (180 or 360 nmol/site) caused object recognition impairment, neuronal death and reactive astrogliosis. A single injection of spermine (0.1 and 1 nmol/site), 5 days after QA injection, reversed QA-induced impairment of object recognition task. Spermine (0.1 nmol/site) also inhibited QA-induced reactive astrogliosis measured by a semi-quantitative determination of GFAP immunolabelling, but did not alter neuronal death, measured by a semi-quantitative determination of fluoro-Jade C staining. These results suggest that polyamine binding sites may be considered a novel therapeutic target to prevent reactive astrogliosis and mnemonic deficits in HD.

Acute intrastriatal administration of quinolinic acid affects the expression of the coat protein AP-2 and its interaction with membranes

Clathrin-coated vesicle endocytosis is thought to be crucial for the maintenance of synaptic transmission and for the cell plasticity at the nervous system. In this study, we demonstrated that acute intrastriatal administration of quinolinic acid (QUIN), an agonist of the N-methyl-D: -aspartate receptor, induces a decrease of the coat protein AP-2 expression and affects their interaction with membranes. By western blot analysis we observed that at 24 h after QUIN intrastriatal injection, alpha1 subunit of AP-2 and alpha2, at lesser extent, were reduced in the striatal membranes. The decrease of both subunits expression was extended to 48 h after treatment, although the soluble proteins were mostly affected. Other areas of the brain were not affected by the treatment, except the cerebellum, where a significant increase of soluble AP-2 (both subunits) was observed at 48 h after injection. Another coat protein, as the phosphoprotein AP-180, was not affected by the injection of QUIN. We also confirmed that QUIN injection causes increasing loss of striatal neurons after the administration of the toxin. We concluded that QUIN may affect the endocytotic machinery of the striatum, by inducing changes in the AP-2 behaviour. Consequently, the internalization of NMDAR and/or AMPAR may be affected, by QUIN, contributing to the excitotoxic effect of the drug.

In vivo imaging of adenosine A2A receptors in rat and primate brain using [11C]SCH442416

The aim of this study was to evaluate the suitability of [11C]SCH442416 for the in vivo imaging of adenosine A2A receptors. In rats and Macaca nemestrina, we evaluated the time course of the cerebral distribution of [11C]SCH442416. Furthermore, in rats we investigated the rate of metabolic degradation, the inhibitory effects of different drugs acting on adenosine or dopamine receptors and the modification induced by the intrastriatal administration of quinolinic acid (QA). The rate of metabolic degradation of [11C]SCH442416 in rats was slow; 60 min after tracer injection, more than 40% of total plasma activity was due to unmetabolised [11C]SCH442416. At the time of maximum uptake, radioactive metabolites represented only 6% of total extractable activity in the cerebellum and less than 1% in the striatum. In the striatum, the region with the highest expression of A2A receptors, the in vivo uptake of [11C]SCH442416 was significantly reduced only by drugs acting on A2A receptors or by QA, a neurotoxin that selectively reduces the number of intrastriatal GABAergic neurons. Position emission tomography (PET) studies in monkeys indicated that the tracer rapidly accumulates in brain, reaching maximum uptake between 5 and 10 min. Twenty minutes after the injection, radioactivity concentration in the striatum was two times that in the cerebellum. The specificity of binding, the rank order of regional distribution in the brain of rats and M. nemestrina, the good signal to noise ratios and the low amount of radioactive metabolites in brain and periphery indicate that [11C]SCH442416 is a promising tracer for the in vivo imaging of A2A adenosine receptors using PET.

Dose-Dependent Neuroprotective Effect of Ciliary Neurotrophic Factor Delivered via Tetracycline-Regulated Lentiviral Vectors in the Quinolinic Acid Rat Model of Huntington's Disease

The ability to regulate gene expression constitutes a prerequisite for the development of gene therapy strategies aimed at the treatment of neurologic disorders. In the present work, we used tetracycline (Tet)-regulated lentiviral vectors to investigate the dose-dependent neuroprotective effect of human ciliary neurotrophic factor (CNTF) in the quinolinic acid (QA) model of Huntington's disease (HD). The Tet system was split in two lentiviruses, the first one containing the CNTF or green fluorescent protein (GFP) cDNAs under the control of the Tet-response element (TRE) and a second vector encoding the transactivator (tTA). Preliminary coinfection study demonstrated that 63.8% +/- 2.0% of infected cells contain at least two viral copies. Adult rats were then injected with CNTF- and GFP-expressing viral vectors followed 3 weeks later by an intrastriatal administration of QA. A significant reduction of apomorphine-induced rotations was observed in the CNTF-on group. In contrast, GFP-treated animals or CNTF-off rats displayed an ipsilateral turning behavior in response to apomorphine. A selective sparing of DARPP-32-, choline acetyltransferase (ChAT)-, and NADPH-d-positive neurons was observed in the striatum of CNTF-on rats compared to GFP animals and CNTF-off group. Enzyme-linked immunosorbent assay (ELISA) performed on striatal samples of rats sacrificed at the same time point indicated that this neuroprotective effect was associated with the production of 15.5 +/- 4.7 ng CNTF per milligram of protein whereas the residual CNTF expression in the off state (0.54 +/- 0.02 ng/mg of protein) was not sufficient to protect against QA toxicity. These results establish the proof of principle of neurotrophic factor dosing for neurodegenerative diseases and demonstrate the feasibility of lentiviral-mediated tetracycline-regulated gene transfer in the brain.

Excitotoxic and metabolic damage to the rodent striatum: role of the P75 neurotrophin receptor and glial progenitors.

After injury, the striatum displays several morphologic responses that may play a role in both regenerative and degenerative events. One such response is the de novo expression of the low-affinity p75 neurotrophin receptor (p75(NTR)), a gene that plays critical roles in central nervous system (CNS) cell death pathways. The present series of experiments sought to elucidate the cellular origins of this p75(NTR) response, to define the conditions under which p75(NTR) is expressed after striatal injury, and how this receptor expression is associated with neuronal plasticity. After chemical lesions, by using either the excitotoxin quinolinic acid (QA) or the complex II mitochondria inhibitor 3-nitropropionic acid (3-NP), we compared the expression of the p75(NTR) receptor within the rat striatum at different survival times. Intrastriatal administration of QA between 7 days and 21 days postlesion induced p75(NTR) expression in astrocytes that was preferentially distributed throughout the lesion core. P75(NTR) immunoreactivity within astrocytes was seen at high (100-220 nmol) but not low (50 nmol) QA doses. Seven and 21 days after 3-NP lesions, p75(NTR) expression was present in astrocytes at all doses tested (100-1,000 nmol). However, in contrast to QA, these cells were located primarily around the periphery of the lesion and not within the lesion core. At the light microscopic level p75(NTR) immunoreactive elements resembled vasculature: but did not colocalize with the pan endothelium cell marker RecA-1. In contrast, p75(NTR)-containing astrocytes colocalized with nestin, vimentin, and 5-bromo-2-deoxyuridine, indicating that these cells are newly born astrocytes. Additionally, striatal cholinergic neurons were distributed around the lesion core expressed p75(NTR) 3-5 days after lesion in both QA and 3-NP lesions. These cells did not coexpress the pro-apoptotic degradation enzyme caspase-3. Taken together, these data indicate that striatal lesions created by means of excitotoxic or metabolic mechanisms trigger the expression of p75(NTR) in structures related to progenitor cells. The expression of the p75(NTR) receptor after these chemical lesions support the concept that this receptor plays a role in the initiation of endogenous cellular events associated with CNS injury.

Ebselen blocks the quinolinic acid-induced production of thiobarbituric acid reactive species but does not prevent the behavioral alterations produced by intra-striatal quinolinic acid administration in the rat

Ebselen (EBS) is a seleno-organic compound with glutathione peroxidase-like activity which is neuroprotective in acute stroke ischemia. In this study, we investigated the effect of EBS on quinolinic acid (QA)-induced neurotoxicity. EBS inhibited QA-induced production of thiobarbituric acid reactive species (TBARS) by striatal homogenates in vitro with an IC 50 of 1.85 μM. Intra-striatal injection of QA (360 nmol) increased striatal content of TBARS and induced convulsions and contralateral rotational behavior. Intra-striatal pre-injection of EBS (10 nmol) 15 min before QA abolished QA-induced TBARS production but did not alter QA-induced behavioral effects. The present findings suggest that EBS acts on post-receptor events, neutralizing free radicals produced by overstimulation of N-methyl- d-aspartate receptors.

Comparison of intrastriatal injections of quinolinic acid and 3-nitropropionic acid for use in animal models of Huntington's disease

1. 1. The present study compared the effects of acute intrastriatal administration of quinolinic acid (QA) and 3-nitropropionic acid (3-NP), two neurotoxins used in animal models of Huntington's disease (HD), on the following behavioral and histological measures: (1) open field activity levels; (2) performance on balance beam and grip strength tasks; (3) acquisition of a radial-arm-water-maze (RAWM) task; (4) size of striatum and lateral ventricles; (5) amount of cytochrome oxidase (CYO) labeling; and (6) counts of Nissl-stained neurons and NADPH-diaphorase-labeled neurons in the striatum. 2. 2. Rats were given bilateral intrastriatal injections of either 200 nmol QA, 750 nmol 3-NP, or phosphate buffered saline (PBS) two weeks prior to behavioral testing and four weeks prior to histological processing. 3. 3. The behavioral results indicated that both QA and 3-NP injections caused an increase in activity levels at two weeks postlesion, but only the QA rats showed hyperactivity at four weeks postlesion. Both QA and 3-NP rats showed significant impairment in the balance beam task, but only 3-NP rats differed significantly on the grip-strength task. Both toxins caused learning impairments in the RAWM task, with 3-NP rats being more severely impaired. 4. 4. The neuroanatomical results indicated that both QA and 3-NP produced significant striatal atrophy and ventricular dilation, as well as a reduction in CYO staining and loss of Nissl-stained neurons, but only the 3-NP lesions created necrotic cavities in the striatum. However, the QA treatments resulted in significant loss of NADPH-diaphorase neurons in regions peripheral to the site of injection. 5. 5. In general, these results suggest that QA treatments produce milder behavioral and neuroanatomical effects that mimic some of the earlier symptoms of HD, while 3-NP produced more severe effects which mimic both the later symptoms and the juvenile onset of HD.

Chronic Administration of Quinolinic Acid in the Rat Striatum Causes Spatial Learning Deficits in a Radial Arm Water Maze Task

Chronic intrastriatal administration of quinolinic acid (QA) in the rat produces a pattern of neurodegeneration similar to that seen in Huntington's disease (HD). Although these changes have been related to transient motor abnormalities, the effects of chronic QA administration on cognitive abilities have not been assessed. The present study investigated whether the striatal deterioration observed during chronic QA administration produces cognitive impairments in this animal model of HD by testing the effects of chronic administration of QA on spatial learning ability of rats in a radial arm water maze (RAWM) task. Rats were given bilateral implantation of a chronic dialysis probe apparatus which delivered either vehicle or QA (20 mM) into the striatum. Beginning 1 day after implantation, the rats were tested daily for 3 weeks in the RAWM. Nocturnal activity levels were also assessed at 1-, 3-, 5-, 7-, 14-, and 21-days following probe implantation. Results of behavioral testing indicated that chronic exposure to QA causes spatial learning deficits in the RAWM task with only a transient increase in activity levels. Collectively, these results suggest that chronic striatal exposure to QA mimics some aspects of the cognitive deficits observed in HD.

The neuronal NOS inhibitor l-MIN, but not 7-NINA, reduces neurotoxic effects of chronic intrastriatal administration of quinolinic acid

Rat striata were exposed to 15 mM quinolinic acid (QUIN), or QUIN plus the nitric oxide synthase inhibitors S-methyl-l-thiocitrulline dihydrochloride (l-MIN) or 7-nitroindazole monosodium salt (7-NINA) for 21 days. Co-administration of 100 μM or 1 mM l-MIN with QUIN significantly reduced lesion volume compared to QUIN alone. Co-administration of 1 μM or 10 μM l-MIN with QUIN had no significant effect. There was no significant effect of 7-NINA co-administered with QUIN compared to QUIN alone. l-MIN reduction of lesion volume supports the contention that neuronal nitric oxide synthase is a mediator of excitotoxic injury.

Chronic intrastriatal administration of quinolinic acid produces transient nocturnal hypermotility in the rat

Adult male Sprague-Dawley rats were exposed to 15 mM quinolinic acid solution or vehicle via bilateral intrastriatal dialytic administration for a period of 3 weeks. Animals were tested twice weekly for spontaneous behaviors and nocturnal activity during the 3-week dialysis period and for the 3 weeks following cessation of the dialysis period treatment. Nocturnal activity increased significantly ( p < 0.005) during the first week of quinolinic acid exposure compared to vehicle exposed animals. The increase in nocturnal activity subsequently diminished to near control levels by the end of the 3-week dialysis period. During the 3-week period following cessation of dialysis, no significant differences were seen between quinolinic acid and vehicle-exposed animals. In addition, no differences were noted between quinolinic acid and vehicle-exposed animals in spontaneous behaviours either in the 3-week dialysis period or the 3-week period following cessation of dialysis. The results of this study are in agreement with other recent findings of transient nocturnal hyperactivity following striatal damage in rats. One possible explanation for the transient nature of this behavioral change is a transient effect of excitotoxicity in the striatum. During initial exposure to excitotoxins, nocturnal hypermotility could result from premorbid changes in neural function. With continued exposure, this behavioral effect may then diminish as a result of subsequent widespread striatal cell death.

Chronic intrastriatal quinolinic acid produces reversible changes in perikaryal calbindin and parvalbumin immunoreactivity

We recently reported the use of a chronic dialytic delivery system for intrastriatal administration of quinolinic acid in the rat. This system produces neurodegeneration with some characteristics similar to post mortem brain tissue from Huntington's disease patients, including reduced cytochrome oxidase staining, a decreased number of Nissl-stained neurons, and relative sparing of striatal NADPH-diaphorase containing neurons. The present findings show that chronic dialytic delivery of quinolinic acid also produces a Huntington's disease-like pattern of reduced calbindin and parvalbumin perikaryal immunoreactivity that is reversed in rats allowed four to eight weeks' recovery after cessation of quinolinic acid. Furthermore, cytochrome oxidase staining and the number of Nissl-stained cells were unchanged in the region of transient calbindin and parvalbumin immunoreactive perikaryal staining alterations. These results suggest that changes in calbindin and parvalbumin perikaryal immunoreactivity provide a relatively sensitive measure of quinolinic acid induced neurotoxicity. The reversible nature of reduced perikaryal immunoreactivity suggests a premorbid state of neurotoxicity, possibly marked by cellular redistribution of calbindin and parvalbumin.