Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis.
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.
Walters
Claire E
CE
Department of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL.
Pryce
Gareth
G
Neuroinflammation Group, Department of Neurochemistry, Institute of Neurology, University College London, 1 Wakefield Street London WC1N 1PJ.
Hankey
Deborah J R
DJR
Neuroinflammation Group, Department of Neurochemistry, Institute of Neurology, University College London, 1 Wakefield Street London WC1N 1PJ.
Sebti
Said M
SM
Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, Departments of Oncology and Biochemistry & Molecular Biology, University of South Florida, 12002 Magnolia Drive, Tampa, Florida 33612-9497 USA.
Hamilton
Andrew D
AD
Department of Chemistry, Yale University, New Haven, CT. USA.
Baker
David
D
Neuroinflammation Group, Department of Neurochemistry, Institute of Neurology, University College London, 1 Wakefield Street London WC1N 1PJ.
Greenwood
John
J
Department of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL.
Adamson
Peter
P
Department of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL.
D000208:Acute Disease; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D004676:Myelin Basic Protein / Q000633:toxicity; D017368:Protein Prenylation / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology
D001549:Benzamides; D004338:Drug Combinations; D004791:Enzyme Inhibitors; C096856:FTI 277; C102521:GGTI 298; D004676:Myelin Basic Protein; D008715:Methionine; D004122:Dimethylallyltranstransferase; D020741:rho GTP-Binding Proteins