Abstract
The ICAM-1-mediated brain endothelial cell (EC)-signaling pathway induced by adherent lymphocytes is a central element in facilitating lymphocyte migration through the tight endothelial barrier of the brain. Rho proteins, which must undergo posttranslational prenylation to be functionally active, have been shown to be an essential component of this signaling cascade. In this study, we have evaluated the effect of inhibiting protein prenylation in brain ECs on their ability to support T lymphocyte migration. ECs treated in vitro with protein prenylation inhibitors resulted in a significant reduction in transendothelial T lymphocyte migration. To determine the therapeutic potential of this approach, an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis, was induced in Biozzi ABH mice. Animals treated before disease onset with protein prenylation inhibitors exhibited a dramatic and significant reduction in both leukocyte infiltration into the CNS and clinical presentation of disease compared with untreated animals. These studies demonstrate, for the first time, the potential for pharmacologically targeting CNS EC signaling responses, and particularly endothelial Rho proteins, as a means of attenuating leukocyte recruitment to the CNS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Animals
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Benzamides / pharmacology
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Brain / drug effects
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Brain / enzymology
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Brain / immunology*
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Brain / pathology
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Cell Line
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Cell Membrane / drug effects
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Cell Membrane / enzymology
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Cell Membrane / metabolism
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Cell Movement / drug effects
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Cell Movement / immunology*
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Dimethylallyltranstransferase / antagonists & inhibitors*
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Disease Models, Animal
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Drug Combinations
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Encephalomyelitis, Autoimmune, Experimental / enzymology
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Encephalomyelitis, Autoimmune, Experimental / prevention & control*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology
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Endothelium, Vascular / metabolism
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Enzyme Inhibitors / pharmacology*
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Guinea Pigs
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Leukocytes / cytology
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Leukocytes / drug effects
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Leukocytes / enzymology
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Leukocytes / immunology*
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Methionine / analogs & derivatives*
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Methionine / pharmacology
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Mice
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Mice, Inbred Strains
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Multiple Sclerosis / enzymology
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Multiple Sclerosis / immunology
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Multiple Sclerosis / pathology
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Multiple Sclerosis / prevention & control
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Myelin Basic Protein / toxicity
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Protein Prenylation / drug effects
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Protein Prenylation / immunology*
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Rats
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Rats, Inbred Lew
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology
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rho GTP-Binding Proteins / antagonists & inhibitors*
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rho GTP-Binding Proteins / physiology
Substances
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Benzamides
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Drug Combinations
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Enzyme Inhibitors
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FTI 277
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GGTI 298
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Myelin Basic Protein
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Methionine
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Dimethylallyltranstransferase
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rho GTP-Binding Proteins