Intrastriatal Injections of Quinolinic Acid or Kainic Acid: Differential Patterns of Cell Survival and the Effects of Data Analysis on Outcome

Roberts, R. M.; Ahn, Andrew H.; Swartz, KJ; Mf, Beal; DiFiglia, Marian

doi:10.1006/exnr.1993.1197

Cited by 87 publications

(37 citation statements)

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“…203 We have begun to investigate this possibility in one of the leading rat models of HD, namely, quinolinic acid (QA) striatal lesion. 131,[204][205][206] We showed that bilateral electrolytic lesions to the rat globus pallidus (GP, the rat analog of the primate GPe) ameliorated the deleterious effects of bilateral QA striatal lesion on several behavioral measures (postsurgery weight, activity level, and performance in a water maze task). 207 We have recently found that an excitotoxic (axon sparing) lesion of the rat GP has the same ameliorating effect as an electrolytic GP lesion, and that this ameliorating effect is obtained both when the GP is lesioned simultaneously with the striatum and when it is lesioned 1 month following the striatal lesion; moreover, this ameliorating effect is also obtained when the GP is inactivated by intrapallidal injection of muscimol (manuscript in preparation).…”

Section: Lesion Of the Associative Gpe: A Potentialmentioning

confidence: 99%

Open interconnected model of basal ganglia‐thalamocortical circuitry and its relevance to the clinical syndrome of Huntington's disease

Joel

2001

Movement Disorders

145

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The early stages of Huntington's disease (HD) present with motor, cognitive, and emotional symptoms. Correspondingly, current models implicate dysfunction of the motor, associative, and limbic basal ganglia-thalamocortical circuits. Available data, however, indicate that in the early stages of the disease, striatal damage is mainly restricted to the associative striatum. Based on an open interconnected model of basal ganglia-thalamocortical organization, we provide a detailed account of the mechanisms by which associative striatal pathology may lead to the complex pattern of motor, cognitive, and emotional symptoms of early HD. According to this account, the degeneration of a direct and several indirect pathways arising from the associative striatum leads to impaired functioning of: (1) the motor circuit, resulting in chorea and bradykinesia, (2) the associative circuit, resulting in abnormal eye movements, "frontal-like" cognitive deficits and "cognitive disinhibition," and (3) the limbic circuit, resulting in affective and psychiatric symptoms. When relevant, this analysis is aided by comparing the symptomatology of HD patients to that of patients with mild to moderate Parkinson's disease, since in the latter there is similar dysfunction of direct pathways but opposite dysfunction of indirect pathways. Finally, we suggest a potential novel treatment of HD and provide supportive evidence from a rat model of the disease.

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Section: Lesion Of the Associative Gpe: A Potentialmentioning

confidence: 99%

Open interconnected model of basal ganglia‐thalamocortical circuitry and its relevance to the clinical syndrome of Huntington's disease

Joel

2001

Movement Disorders

145

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“…Quinolinic acid (QA) could induce lesions similar as the behavioral, morphological and neurochemical alterations in HD patients, including hyperactivity [2] , cognitive impairment [3] , depletion of spiny neuron markers [1,4] , and reduction in GABAergic and cholinergic neurotransmission [5,6] . Hyperstimulation of NMDA receptors [7] leads to massive Ca 2+ influxes that would then activate other cellular processes, such…”

Section: Introductionmentioning

confidence: 99%

Effects of caffeic acid, rofecoxib, and their combination against quinolinic acid-induced behavioral alterations and disruption in glutathione redox status

Kalonia

Kumar

et al. 2009

Neurosci. Bull.

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Objective The neuroprotective roles of cyclooxygenase (COX) and lipooxygenase (LOX) inhibitors have been well documented. Quinolinic acid (QA) is a well-known excitotoxic agent that could induce behavioral, morphological and biochemical alterations similar with symptoms of Huntington's disease (HD), by stimulating NMDA receptors. However, the exact roles of COX and LOX inhibitors in HD have not yet been explained. The present study aims to elucidate the effects of caffeic acid (a specific inhibitor for LOX), rofecoxib (a specific inhibitor for COX-2), and their combination in ameliorating QAinduced neurotoxicity in rats. Methods QA was injected into the right striatum of rats to induce neurotoxicity. Caffeic acid and rofecoxib were then orally administered separately. In the combination study, caffeic acid and rofecoxib were administered together. After that, a series of behavioral assessments were conducted to determine the effects of caffeic acid and rofecoxib, respectively, and the co-effect of caffeic acid and rofecoxib, against QA-induced neurotoxicity. Results Intrastriatal QA administration (300 nmol) not only induced a significant reduction in body weight and motor incoordination, but also altered the redox status (decreased glutathione and increased oxidized glutathione level) in striatum, as compared to the sham group.Moreover, chronic treatment with caffeic acid (5 mg/kg and 10 mg/kg, respectively, p.o.) or rofecoxib (10 mg/kg, p.o.) could significantly attenuate QA-induced behavioral alterations and restore the redox status in striatum. However, at the dose of 2.5 mg/kg, caffeic acid did not show any significant effects on these parameters in QA-treated rats. Furthermore, the combination of rofecoxib (10 mg/kg) and caffeic acid (5 mg/kg) could significantly protect against QA neurotoxicity. Conclusion The in vivo study indicates that excitotoxic injury to the brain might affect oxidant/antioxidant equilibrium by eliciting changes in glutathione. Moreover, the LOX and the COX pathways may be both involved in quinolinic-induced neurotoxicity, which provides a promising target for HD treatment.

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“…The most potent endogenous excitotoxin discovered so far is quinolinic acid (QUIN), a selective N-methyl-oaspartate (NMDA) receptor agonist (Stone and Perkins, 1981;Wolfensberger et al, 1983) which readily produces axon-sparing neuronal destruction in the rat striatum . Since QUIN-induced striatal lesions mimic many of the neuropathological features of HD Beal et al, 1986;Roberts et al, 1993) QUIN has been implicated in the neurodegeneration occurring in HD. The enzyme directly responsible for the synthesis of QUIN, 3-hydroxyanthranilic acid oxygenase (3HAO), is present in brain tissue (Foster et al, 1986), and its activity is substantially elevated in the brain of HD victims .…”

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confidence: 99%

3-Hydroxyanthranilic acid oxygenase-containing astrocytic processes surround glutamate-containing axon terminals in the rat striatum

Roberts

McCarthy

et al. 1995

J. Neurosci.

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Glutamate, the major transmitter of the corticostriatal pathway, is present in abundance in the striatum. 3-Hydroxyanthranilic acid oxygenase (3HAO) is the biosynthetic enzyme for quinolinic acid, an endogenous agonist of the NMDA glutamate receptor subtype and a potent neurotoxin. In order to explore the anatomical basis of possible functional interactions between glutamate and quinolinic acid in the rat striatum, pre- and postembedding immunocytochemical methods were used to localize 3HAO immunoreactivity (-i) and glutamate-i at the electron microscopic level. In accordance with previous light microscopic and biochemical studies, 3HAO-i was detected exclusively in astrocytes throughout the striatum. Notably, 3HAO-i was present in fine- caliber glial processes that often surrounded or abutted synaptic profiles, both asymmetric and symmetric. Glutamate-i was heavily deposited (3–13-fold higher gold particle density than tissue average) in axon terminals forming asymmetric synapses with spines and, occasionally, dendrites. In contrast, terminals forming symmetric synapses, dendrites, neuronal somata, and glial cells contained significantly less labeling than terminals forming asymmetric synapses. In double-labeled material, 3HAO-i was observed in glial processes that partially surrounded or were adjacent to glutamate-labeled terminals forming asymmetric synapses. 3HAO-labeled glial processes were also adjacent to unlabeled terminals forming symmetric synapses. Since quinolinic acid is known to enter the extracellular compartment readily, these results suggest that astrocytic quinolinic acid may participate in the regulation of glutamatergic neurotransmission in the rat striatum.

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Intrastriatal Injections of Quinolinic Acid or Kainic Acid: Differential Patterns of Cell Survival and the Effects of Data Analysis on Outcome

Cited by 87 publications

References 0 publications

Open interconnected model of basal ganglia‐thalamocortical circuitry and its relevance to the clinical syndrome of Huntington's disease

Open interconnected model of basal ganglia‐thalamocortical circuitry and its relevance to the clinical syndrome of Huntington's disease

Effects of caffeic acid, rofecoxib, and their combination against quinolinic acid-induced behavioral alterations and disruption in glutathione redox status

3-Hydroxyanthranilic acid oxygenase-containing astrocytic processes surround glutamate-containing axon terminals in the rat striatum

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