Abstract
Excitotoxic brain lesions initially result in the primary destruction of brain parenchyma, after which microglial cells migrate towards the sites of injury. At these sites, the cells produce large quantities of oxygen radicals and cause secondary damage that accounts for most of the loss of brain function. Here we show that this microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, regulated by the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) through the formation of a nuclear PARP-NF-kappaB-protein complex. Downregulation of PARP or CD11a by transfection with antisense DNA abrogated microglial migration almost completely and prevented neurons from secondary damage.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain Diseases / physiopathology
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Cell Movement / physiology
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Cells, Cultured
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DNA, Antisense
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Excitatory Amino Acid Agonists / pharmacology
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Gene Expression / physiology
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Lymphocyte Function-Associated Antigen-1 / genetics*
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Mice
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Microglia / cytology
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Microglia / physiology*
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N-Methylaspartate / pharmacology
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NF-kappa B / metabolism
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Nerve Degeneration / physiopathology
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Neurotoxins / pharmacology
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Phagocytosis / physiology
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Poly(ADP-ribose) Polymerases / metabolism*
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RNA, Messenger / analysis
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Transfection
Substances
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DNA, Antisense
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Excitatory Amino Acid Agonists
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Lymphocyte Function-Associated Antigen-1
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NF-kappa B
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Neurotoxins
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RNA, Messenger
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N-Methylaspartate
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Poly(ADP-ribose) Polymerases