Abstract
Prolonged activation of brain N-methyl-D-aspartic acid (NMDA) receptors increases intraneuronal (Ca2+) and nitric oxide (NO) synthesis, and may be responsible for neuronal death in acute brain insults and chronic neurodegenerative diseases. NO can be converted in vitro to toxic hydroxyl (OH) radical. Using microdialysis of striatum in awake animals, we found that local NMDA receptor activation increased outflow of OH radicals four-fold. NMDA-stimulated OH production was blocked by inhibitors of nitric oxide synthase (NOS) and protein kinase C (PKC). NMDA receptor-mediated neuronal death may derive from NOS- and PKC-dependent synthesis of OH radicals.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkaloids / pharmacology
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Amino Acid Oxidoreductases / metabolism*
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Analysis of Variance
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Animals
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism*
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Dizocilpine Maleate / pharmacology*
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Hydroxyl Radical / metabolism*
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Male
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N-Methylaspartate / pharmacology*
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Neurons / drug effects
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Neurons / metabolism
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Nitric Oxide Synthase
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism*
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Rats
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Receptors, N-Methyl-D-Aspartate / drug effects
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Receptors, N-Methyl-D-Aspartate / physiology*
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Staurosporine* / analogs & derivatives*
Substances
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Alkaloids
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Receptors, N-Methyl-D-Aspartate
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CGP 42700
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Hydroxyl Radical
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N-Methylaspartate
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Dizocilpine Maleate
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Nitric Oxide Synthase
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Amino Acid Oxidoreductases
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Protein Kinase C
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Staurosporine
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midostaurin