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  • 2000-2004  (3)
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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Nigrostriatal dopaminergic denervation is associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. The excitatory neurotransmitter glutamate mediates neural signaling at crucial points of this circuitry, and glutamate receptors are differentially distributed in the basal ganglia. Available evidence suggests that the glutamatergic corticostriatal and subthalamofugal pathways become overactive after nigrostriatal dopamine depletion. In this study, we have analyzed the regulation of the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor in the basal ganglia of primates following 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine-induced dopamine denervation. The dopamine denervation resulted in distinct alterations in GluR1 distribution: (1) GluR1 protein expression was markedly increased in caudate and putamen, and this was most pronounced in the striosomes; (2) GluR1 protein was altered minimally in subthalamic nucleus; (3) expression of GluR1 was down-regulated in the globus pallidus by 63% and in the substantia nigra by 57%. The down-regulation of GluR1 expression in the output nuclei of the basal ganglia, the internal segment of the globus pallidus and the substantia nigra pars reticulata, may be a compensation for the overactive glutamatergic input from subthalamic nucleus, which arises after striatal dopamine denervation. Our results indicate that the glutamatergic system undergoes regulatory changes in response to altered basal ganglia activity in a primate model of Parkinson's disease. Targeted manipulation of the glutamatergic system may be a viable approach to the symptomatic treatment of Parkinson's disease.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : In Parkinson's disease, there is a selective defect in complex I of the electron transfer chain. To better understand complex I and its involvement in neurodegenerative disease, we raised an antibody against a conserved epitope of the human mitochondrially encoded subunit 1 of complex I (ND1). Antibodies were affinity purified and assessed by ELISA, immunoblotting, and immunocytochemistry. Immunoblots of brain homogenates from mouse, rat, and monkey brain showed a single 33-kDa band consistent with the predicted molecular mass of the protein. Subcellular fractionation showed the protein to be enriched in mitochondria. Immunocytochemistry in rat brain revealed punctate labeling in cell bodies and processes of neurons. Immunoreactively generally co-localized with subunit IV of complex IV. In striatum, ND1 immunoreactively was greatly enriched in large cholinergic neurons and neurons containing nitric oxide synthase, two cell populations that are resistant to excitotoxic and metabolic insults. In substantia nigra, many dopaminergic neurons had little ND1 immunoreactivity, which may help to explain their sensitivity to complex I inhibitors. In spinal cord, ND1 immunoreactively was enriched in motor neurons. We conclude that complex I is differentially distributed across brain regions, between neurons and glia, and between types of neurons. This antibody should provide a valuable tool for assessing complex I in normal and pathological conditions.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Defects in mitochondrial energy metabolism have beenimplicated in several neurodegenerative disorders. Defective complex I(NADH:ubiquinone oxidoreductase) activity plays a key role in Leber'shereditary optic neuropathy and, possibly, Parkinson's disease, but there isno way to assess this enzyme in the living brain. We previously described anin vitro quantitative autoradiographic assay using[3H]dihydrorotenone ([3H]DHR) binding to complex I. Wehave now developed an in vivo autoradiographic assay for complex I using[3H]DHR binding after intravenous administration. In vivo[3H]DHR binding was regionally heterogeneous, and brain uptake wasrapid. Binding was enriched in neurons compared with glia, and white matterhad the lowest levels of binding. In vivo [3H]DHR binding wasmarkedly reduced by local and systemic infusion of rotenone and was enhancedby local NADH administration. There was an excellent correlation betweenregional levels of in vivo [3H]DHR binding and the in vitroactivities of complex II (succinate dehydrogenase) and complex IV (cytochromeoxidase), suggesting that the stoichiometry of these components of theelectron transport chain is relatively constant across brain regions. Theability to assay complex I in vivo should provide a valuable tool toinvestigate the status of this mitochondrial enzyme in the living brain andsuggests potential imaging techniques for complex I in humans.
    Type of Medium: Electronic Resource
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