Lovastatin inhibits brain endothelial cell Rho‐mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis

• DOI: 10.1096/fj.02-1014fje
• Publication Date: 2003-04-30T20:03:40Z
• Authors: John Greenwood; Claire E. Walters; Gareth Pryce; Naheed Kanuga; Evelyne Bemud; David Baker; Peter Adamson
• Keywords: Lovastatin; Mevalonate pathway

Neuroinflammatory diseases, such as multiple sclerosis (MS), result from aberrant leukocyte traffic into the central nervous system (CNS). To breach specialized blood-brain barrier, activated leukocytes interact with CNS endothelial cells (EC) and activate a CD54-mediated signaling pathway controlling Rho GTPase. function correctly requires posttranslational prenylation, this can be inhibited by depleting supply of isoprenoids through inhibition cholesterol synthesis 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) inhibitors (statins). Here we show that treatment brain EC in vitro lovastatin inhibits Rho-mediated transendothelial T cell migration. This effect reversed supplementation mevalonolactone, downstream product HMG-CoA reductase, or ectopic expression myristoylated Rho, which remains active absence prenylation. In relapsing-remitting mouse model MS, migration significantly attenuated development both acute relapsing clinical disease. These studies demonstrate indirect pharmacological proteins statins inhibit key stage pathogenesis neuroinflammation, namely across barrier. novel modulating immune response neuroinflammtory diseases may provide additional rationale for their use MS.