Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acids

McGeer, Edith G.; McGeer, P. L.

doi:10.1038/263517a0

Cited by 806 publications

(166 citation statements)

References 7 publications

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“…Intrastriatal infusion of KA can induce excitotoxic lesions in the striatum and has become a well-established chemical model of HD [71,72] . In studies of post-receptor mechanisms of excitotoxicity, our laboratory has found that KA-or the NMDA receptor agonist quinolinic acid (QA)-induced neuronal apoptosis involves activation of NF-κB and induction of p53, c-Myc, and other proapoptotic proteins [73][74][75] , which seems to mimic HD pathology.…”

Section: Excitotoxicity In Neurodegenerative Diseasesmentioning

confidence: 99%

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

2009

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A pivotal role for excitotoxicity in neurodegenerative diseases is gaining increasingly more acceptance, but the underlying mechanisms through which it participates in neurodegeneration still need further investigation. Excessive activation of glutamate receptors by excitatory amino acids leads to a number of deleterious consequences, including impairment of calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and secondary excitotoxicity. Recent studies implicate excitotoxicity in a variety of neuropathological conditions, suggesting that neurodegenerative diseases with distinct genetic etiologies may share excitotoxicity as a common pathogenic pathway. Thus, understanding the pathways involved in excitotoxicity is of critical importance for the future clinical treatment of many neurodegenerative diseases. This review discusses the current understanding of excitotoxic mechanisms and how they are involved in the pathogenesis of neurodegenerative diseases.

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Section: Excitotoxicity In Neurodegenerative Diseasesmentioning

confidence: 99%

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

2009

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“…However, recent findings have reported that the variance in the age of onset of HD could also be attributed to mutations in the gene encoding the GluR6 KAR subunit (Rubinsztein et al, 1997;MacDonald et al, 1999). Injections of kainic acid into the striatum have, indeed, been known to cause cell death in striatal projection neurons, but to have no such effect on axons crossing or terminating in the area (Coyle and Schwarcz, 1976;McGeer and McGeer, 1976). The fact that these neurotoxic effects of kainate in the striatum are attenuated after decortication (McGeer et al, 1978;Biziere and Coyle, 1979), implies that these effects are mediated via cortical terminal glutamate release.…”

Section: Abstract: Huntington's Disease; Excitotoxicity; Presynapticmentioning

confidence: 99%

Subcellular and Subsynaptic Localization of Presynaptic and Postsynaptic Kainate Receptor Subunits in the Monkey Striatum

et al. 2001

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The localization and functions of kainate receptors (KARs) in the CNS are still poorly known. In the striatum, GluR6/7 and KA2 immunoreactivity is expressed presynaptically in a subpopulation of glutamatergic terminals and postsynaptically in dendrites and spines. The goal of this study was to further characterize the subcellular and subsynaptic localization of kainate receptor subunits in the monkey striatum. Immunoperoxidase data reveal that the relative abundance of GluR6/7-and KA2-immunoreactive terminals is homogeneous throughout the striatum irrespective of the differential degree of striatal degeneration in Huntington's disease. Pre-embedding and post-embedding immunogold data indicate that Ͼ70% of the presynaptic or postsynaptic GluR6/7 and KA2 labeling is expressed intracellularly. In material stained with the post-embedding immunogold method, approximately one-third of plasma membrane-bound gold particles labeling in axon terminals and spines is associated with asymmetric synapses, thereby representing synaptic kainate receptor subunits. On the other hand, Ͼ60% of the plasmamembrane bound labeling is extrasynaptic. Both GluR6/7 and KA2 labeling in glutamatergic terminals often occurs in clusters of gold particles along the membrane of large vesicular organelles located at various distances from the presynaptic grid. Anterograde labeling from the primary motor cortex or the centromedian thalamic nucleus indicate that both corticostriatal and thalamostriatal terminals express presynaptic GluR6/7 and KA2 immunoreactivity in the postcommissural putamen. In conclusion, these data demonstrate that kainate receptors in the striatum display a pattern of subcellular distribution different from other ionotropic glutamate receptor subtypes, but consistent with their metabotropic-like functions recently shown in the hippocampus.

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“…Under acute disease conditions characterized by some combination of cellular injury, neuronal depolarization, and impaired energy metabolism-for example, hypoxia (Rothman, 1984) hypoglycemia (Wieloch, 1985), or prolonged seizures (Nadler et al, 1978;Sloviter, 1983)-increased synaptic release and reduced cellular uptake may conspire to produce rapidly toxic extracellular glutamate concentrations (Benveniste et al, 1984;Hagberg et al, 1985). More subtle alterations in the glutamate system, for example, abnormal glutamate metabolism, have been postulated to underlie the slow neuronal loss of certain chronic neurodegenerative diseases (McGeer and McGeer, 1976;Olney and De Gubareff, 1978;Plaitakis et al, 1982;DeBoni and McLachlan, 1985). The mechanisms by which excess exposure to glutamate can lead to this potentially important neuronal cell injury are not well understood and depend considerably on extrapolation from the better defined phenomenon of glutamate neuroexcitation.…”

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confidence: 99%

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

1988

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The antagonist pharmacology of glutamate neurotoxicity was quantitatively examined in murine cortical cell cultures. Addition of 1- 3 mM DL-2-amino-5-phosphonovalerate (APV), or its active isomer D-APV, acutely to the exposure solution selectively blocked the neuroexcitation and neuronal cell selectively blocked the neuroexcitation and neuronal cell loss produced by N-methyl-D-aspartate (NMDA), with relatively little effect on that produced by either kainate or quisqualate. As expected, this selective NMDA receptor blockade only partially reduced the neuroexcitation or acute neuronal swelling produced by the broad-spectrum agonist glutamate; surprisingly, however, this blockade was sufficient to reduce glutamate- induced neuronal cell loss markedly. Lower concentrations of APV or D- APV had much less protective effect, suggesting that the blockade of a large number of NMDA receptors was required to acutely antagonize glutamate neurotoxicity. This requirement may be caused by the amplification of small amounts of acute glutamate-induced injury by subsequent release of endogenous NMDA agonists from injured neurons, as the “late” addition of 10–1000 microM APV or D-APV (after termination of glutamate exposure) also reduced resultant neuronal damage. If APV or D-APV were present both during and after glutamate exposure, a summation dose-protection relationship was obtained, showing substantial protective efficacy at low micromolar antagonist concentrations. Screening of several other excitatory amino acid antagonists confirmed that the ability to antagonize glutamate neurotoxicity might correlate with ability to block NMDA-induced neuroexcitation: The reported NMDA antagonists ketamine and DL-2-amino- 7-phosphono-heptanoate, as well as the broad-spectrum antagonist kynurenate, were all found to attenuate glutamate neurotoxicity substantially; whereas gamma-D-glutamylaminomethyl sulfonate and L- glutamate diethyl ester, compounds reported to block predominantly quisqualate or kainate receptors, did not affect glutamate neurotoxicity. The present study suggests that glutamate neurotoxicity may be predominantly mediated by the activation of the NMDA subclass of glutamate receptors--occurring both directly, during exposure to exogenous compound, and indirectly, due to the subsequent release of endogenous NMDA agonists. Given other studies linking NMDA receptors to channels with unusually high calcium permeability, this suggestion is consistent with previous data showing that glutamate neurotoxicity depends heavily on extracellular calcium.

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Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acids

Cited by 806 publications

References 7 publications

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

Subcellular and Subsynaptic Localization of Presynaptic and Postsynaptic Kainate Receptor Subunits in the Monkey Striatum

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

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