Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cultured striatal neurons containing either NADPH-diaphorase or acetylcholinesterase were more resistant to injury by N-methyl-D-aspartate (NMDA) or quinolinate, than the general striatal neuronal population, although this resistance was not absolute and could be overcome by intense toxic exposure. Neurons containing NADPH-diaphorase, but not neurons containing acetylcholinesterase, also exhibited heightened vulnerability to injury by kainate. Given recent evidence that diaphorase- and cholinesterase-containing striatal neurons are selectively spared in Huntington's disease, our results strengthen the possibility that NMDA receptor-mediated neurotoxicity may participate in the pathogenesis of that disease.
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PMID:Cultured striatal neurons containing NADPH-diaphorase or acetylcholinesterase are selectively resistant to injury by NMDA receptor agonists. 283 34

Exposure of cultures of cortical cells from mouse to either of the endogenous excitatory neurotoxins quinolinate or glutamate resulted in widespread neuronal destruction; but only in the cultures exposed to quinolinate, an N-methyl-D-aspartate agonist, was there a striking preservation of the subpopulation of neurons containing the enzyme nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d). Further investigation revealed that neurons containing NADPH-d were also resistant to the toxicity of N-methyl-D-aspartate itself but were selectively vulnerable to the toxicity of either kainate or quisqualate. Thus, neurons containing NADPH-d may have an unusual distribution of receptors for excitatory amino acids, with a relative lack of N-methyl-D-aspartate receptors and a relative preponderance of kainate or quisqualate receptors. Since selective sparing of neurons containing NADPH-d is a hallmark of Huntington's disease, the results support the hypothesis that the disease may be caused by excess exposure to quinolinate or some other endogenous N-methyl-D-aspartate agonist.
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PMID:Neurons containing NADPH-diaphorase are selectively resistant to quinolinate toxicity. 287 22

A distinct subpopulation of striatal aspiny neurons, containing the enzyme nicotinamide adenine dinucleotide phosphate diaphorase, is preserved in the caudate nucleus in Huntington's disease. Biochemical assays confirmed a significant increase in the activity of this enzyme in both the caudate nucleus and putamen in postmortem brain tissue from patients with this disease. The resistance of these neurons suggests that the gene defect in Huntington's disease may be modifiable by the local biochemical environment. This finding may provide insight into the nature of the genetically programmed cell death that is a characteristic of the disease.
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PMID:Selective sparing of a class of striatal neurons in Huntington's disease. 293 2

We have previously found that a biochemically distinct subset of neurons, containing nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), is selectively resistant to the degenerative process that affects the striatum in Huntington's disease (HD). We report the morphologic and histochemical characteristics of these striatal neurons and their distribution with respect to the histochemical compartments as defined by acetylcholinesterase (AChE) activity. Sections of striatum were stained histochemically for NADPH-d and AChE and immunocytochemically for somatostatin and neuropeptide Y-like immunoreactivity. The diaphorase end-product was contained within medium-sized neurons which corresponded morphologically to a category of aspiny interneurons. Combined techniques showed that NADPH-d, somatostatin, and neuropeptide Y coexisted within the same neurons in controls and patients with HD. The density of these neurons was greater in the ventral putamen and the nucleus accumbens than in the remainder of the striatum. The distinctive AChE pattern of high and low enzyme activity was altered in HD. The AChE-rich matrix zone was markedly reduced in size, while the total area of zones of low enzyme activity was not different from that found in control striatum. The relation between these AChE chemical compartments and the distribution of preserved diaphorase neurons remained intact; NADPH-d neurons were predominantly observed in the matrix zone.
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PMID:Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington's disease. 294 77

A combination of immunocytochemical and enzyme histochemical methods have been used to study those neurons which survive lesions of the rat striatum, produced by low doses of the excitotoxin quinolinic acid. Nissl-stained sections revealed that following injection of this toxin many large neurons remained within areas of extensive cell loss. These large cells were found to express both the enzyme acetylcholinesterase and choline acetyltransferase-like immunoreactivity. The surviving cells did not contain the enzyme reduced nicotinamide adenine dinucleotide phosphate or the peptides, somatostatin and neuropeptide Y. This pattern of selective cell sparing was also found following lesions induced by low doses of the toxins ibotenic acid and kainic acid. The survival of large neurons indicates that the excitotoxin-lesioned rat striatum shares common features with the pattern of cell loss found in the caudate-putamen in Huntington's disease. The major difference between these two examples of striatal nerve cell degeneration is, however, the selective preservation of somatostatin/neuropeptide Y/nicotinamide adenine dinucleotide phosphate-diaphorase-containing neurons found in Huntington's disease but not observed following quinolinic acid lesions.
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PMID:Sparing of cholinergic neurons following quinolinic acid lesions of the rat striatum. 297 92

Quantitative concentration-toxicity relationships were determined for the injury of cultured murine cortical neurons by several excitatory amino acid (EAA) agonists. All tested agonists produced concentration-dependent neuronal injury at concentrations between 1 and 1000 microM. With 5 min exposure, glutamate, aspartate, N-methyl-D-aspartate (NMDA), L-homocysteate (HCA), and quisqualate all had similar potencies, destroying half of the neuronal population (LD50) at concentrations of 50-200 microM, and similar efficacies, with 88-92% neuronal loss produced by exposure to high agonist concentrations. Quinolinate and kainate were substantially weaker toxins, producing only 20-30% neuronal loss after 5 min exposure to 3 mM concentrations; with prolonged (24 hr) exposure, 85-95% neuronal loss could be attained. The comparative EAA vulnerability of a specific cortical neuronal subpopulation containing high concentrations of the enzyme, reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), was also examined. Glutamate had no differential toxicity on these cells, damaging them at all concentrations in proportion to the general population; however, other, more selective, agonists produced strikingly differential injuries. These NADPH-d-containing [NADPH-d(+)]neurons were selectively resistant to damage by low concentrations of the NMDA agonists quinolinate, HCA, aspartate, or NMDA itself. By contrast, NADPH-d(+)neurons were selectively destroyed by concentrations of quisqualate or kainate too low to produce much general neuronal injury. The differential susceptibility of these neurons was not absolute, as high concentrations of all tested agonists produced nonselective neuronal injury. In light of recent evidence that forebrain NADPH-d(+)neurons are selectively spared in Huntington's disease, the present study continues to support the hypothesis that neuronal loss in Huntington's disease might result from excessive NMDA-receptor stimulation by any selective NMDA agonist. Furthermore, the demonstration that the differential susceptibility of NADPH-d(+)neurons is agonist concentration-dependent, rather than absolute, could provide a basis for explaining some existing conflicting experimental data.
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PMID:Vulnerability of cultured cortical neurons to damage by excitotoxins: differential susceptibility of neurons containing NADPH-diaphorase. 338 92

Neurons containing reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase and acetylcholinesterase in the striatum are spared in Huntington's disease. It has been claimed that these neurons are also spared after intrastriatal injection of the N-methyl-D-aspartate receptor agonist, quinolinic acid. In the present study the effects of intrastriatal injection of quinolinic acid (15, 30 and 60 nmol) on neurons containing NADPH diaphorase and acetylcholinesterase were examined in rats. Neurons identified histochemically were counted in whole striatal sections at the level of the injection site and at 400 microns intervals anterior and posterior to the injection site. There was a dose-related reduction in the total number of NADPH diaphorase-containing neurons counted in these levels, but only a mild loss of acetylcholinesterase-containing neurons. Acetylcholinesterase-positive neurons were observed near the injection site following administration of all doses. The effects of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (50 mg/kg, i.p. twice daily for seven days), on quinolinic acid (30 nmol. day 5)-induced toxicity were also investigated. Striatal sections were stained for NADPH diaphorase-, nitric oxide synthase- and acetylcholinesterase-containing neurons and cells were counted in whole striatal sections at the level of the injection site and at four levels posterior to the injection site. Nitric oxide synthase activity was measured in striatal homogenates. NG-Nitro-L-arginine methyl ester did not protect against or potentiate the loss of NADPH diaphorase-, nitric oxide synthase- or acetylcholinesterase-containing neurons or the loss in nitric oxide synthase activity. Acute intrastriatal injection of quinolinic acid may not be a suitable model for Huntington's disease and a role for nitric oxide in quinolinic acid-induced toxicity is not supported in this model.
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PMID:The effect of nitric oxide synthase inhibition on quinolinic acid toxicity in the rat striatum. 754 92

In order to establish an in vitro model of Huntington's disease, we prepared slice cultures of striatal tissue from newborn rats. The striatal cultures were grown for 12-39 days in the absence of any other brain tissue. The presence of specific cell markers was shown by immunocytochemistry, histochemistry and in situ hybridization with alkaline-phosphatase-labeled oligonucleotide probes. We focused on (1) the medium-sized, aspiny interneurons, which in vivo express the neuropeptides somatostatin and neuropeptide Y and the nitric oxide synthesizing enzyme nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase, and which are spared in Huntington's disease and (2) the enkephalinergic, medium-sized projection neurons, which are particularly vulnerable in Huntington's disease. Similar basic morphologies of the presumed interneurons and double staining of NADPH-diaphorase positive and somatostatin immunoreactive neurons suggest that the two neuropeptides and NADPH-diaphorase are extensively colocalized in the cultures, as in vivo. In the newborn rats, included as controls, a patch-matrix distribution of the NADPH-diaphorase staining is described for the first time. In the striatal slices the distribution of the NADPH-diaphorase staining stayed uneven after 3-5 weeks in culture, with areas almost devoid of staining alternating with more heavily stained areas. This pattern may represent an intermediate stage between the patch-matrix distribution in the newborn and the homogeneous staining in the adult rat striatum. From quantitative estimates we found the same mutual rank order of the numbers of neuropeptide Y- and somatostatin-immunoreactive neurons and NADPH-diaphorase positive neurons in vivo and in vitro. Both in the slice cultures and in the brain, the number of enkephalin mRNA-containing neurons significantly exceeded that of neuropeptide Y- and somatostatin mRNA-containing neurons. This implies that the mutual distribution of presumed interneurons and projection neurons was preserved in the slice cultures. Comparison of cell numbers per unit volume showed that, in the cultures, the number of presumed interneurons, with the exception of NPY mRNA-containing neurons, significantly exceeded that in vivo. In contrast, the enkephalin mRNA-containing neurons, which in vivo are projection neurons, were significantly fewer in the cultures. The relative loss of projection neurons and preservation of interneurons in single slice cultures of striatal tissue apparently mimick some of the neurodegenerative changes of Huntington's disease.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Organotypic slice cultures of the rat striatum: an immunocytochemical, histochemical and in situ hybridization study of somatostatin, neuropeptide Y, nicotinamide adenine dinucleotide phosphate-diaphorase, and enkephalin. 761 39

Basic parameters which are crucial for the survival of human embryonic striatal grafts need to be investigated before initiating clinical trials in Huntington's disease. In order to define the dissection of human striatal-donor tissue which gives rise to the largest amount of striatal neurons after intrastriatal transplantation, we studied the lateral and medial ganglionic eminences of embryonic striatal primordia obtained from human embryos sized 17-30 mm in crown-to-rump length (corresponding to Carnegie stages 18-23). Anatomical landmarks that demarcated the lateral and medial ganglionic eminences from each other were present only in embryos with 20 mm crown-to-rump length or larger. In monolayer cultures, the lateral ganglionic eminence gave rise to a six-fold higher yield of dopamine- and cyclic AMP-regulated phosphoprotein 32-immunoreactive striatal neurons as compared to the medial ganglionic eminence. We also xenografted the lateral and medial ganglionic eminences from five embryos sized 21-30 mm in crown-to-rump length to the ibotenate lesioned striatum of immunosuppressed rats. The grafts were evaluated with respect to general morphology, survival and integration using (immuno-) histochemical stains for acetylcholinesterase/Cresyl Violet, nicotinamide adenine dinucleotide phosphate-diaphorase, dopamine- and cyclic AMP-regulated phosphoprotein-32, tyrosine hydroxylase and calbindin-D28KD. As assessed 9-25 weeks after implantation, 13 out of 16 and 8 out of 13 grafts, in the groups grafted with the medial and lateral ganglionic eminences, respectively, had survived. Previous studies with rat donor tissue have indicated that the functional efficacy of striatal grafts is related to the development of striatal-specific P-zone regions and that these are enriched in transplants derived from the lateral as opposed to the medial ganglionic eminence. Also in the human striatal xenografts of the present study, P-zones appeared more abundant when the donor tissue was derived from the lateral ganglionic eminence. However, the proportion of graft tissue that expressed P-zone properties was always very low (at most 30%) and never approached the 80-90% previously observed in transplants of rat lateral ganglionic eminence. We conclude that the relative yield of striatal neurons in grafts of the human embryonic striatal primordium has to be improved before neural transplantation should be applied in patients with Huntington's disease.
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PMID:Phenotypic development of the human embryonic striatal primordium: a study of cultured and grafted neurons from the lateral and medial ganglionic eminences. 878 40

It has been suggested that oxidative stress plays an important role in mediating excitotoxic neuronal death. We have therefore investigated the protective effects of antioxidants against excitotoxic injury in the rat on striatal neurons both in vitro and in vivo. In the first part of the study, we determined whether two different types of antioxidants, the spin trapping agent, alpha-phenyl-tert-butyl nitrone and an inhibitor of lipid peroxidation, U-83836E, could protect cultured striatal neurons against either hypoglycemic injury or N-methyl-D-aspartate-induced excitotoxicity. Dopamine- and cyclic AMP-regulated phosphoprotein, which is enriched in medium-sized spiny neurons, was chosen as a marker for striatal neurons. alpha-Phenyl-t-butyl nitrone and U-83836E both significantly reduced cell death induced by these insults as indicated by an increased number of surviving dopamine- and cyclic AMP-regulated phospho-protein-positive neurons. The two antioxidants also promoted the survival of cultured striatal neurons grown at low cell density under serum-free culture conditions. In an in vivo experiment systemically administered alpha-phenyl-t-butyl nitrone exerted neuroprotective effects in the rat striatum following injection of the excitotoxin quinolinic acid. Apomorphine-induced rotation tests revealed that alpha-phenyl-t-butyl nitrone-treated animals were significantly less asymmetric in their motor behavior than control rats. Treatment with alpha-phenyl-t-butyl nitrone significantly reduced the size of the quinolinic acid-induced striatal lesions, as assessed by the degree of sparing of dopamine- and cyclic AMP-regulated phospho-protein-positive and nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons, and of microtubule-associated protein-2-immunorective areas. Furthermore, lesion-induced morphological changes in the substantia nigra pars reticulate, i.e. loss of dopamine- and cyclic AMP-regulated phosphoprotein-positive afferent fibers and atrophic changes due to transsynaptic degeneration, were also less extensive in the alpha-phenyl-t-butyl nitrone-treated animals. The results support the hypothesis that oxygen-free radicals contribute to excitotoxic neuronal injury. The in vivo cytoprotective effects of alpha-phenyl-t-butyl nitrone against striatal excitotoxic lesions suggest that antioxidants could be used as potential neuroprotective agents in Huntington's disease, which has been suggested to involve excitotoxicity.
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PMID:Antioxidant treatment protects striatal neurons against excitotoxic insults. 878 41


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