Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: Relevance to multiple sclerosis

Igal Ifergan, Karolina Wosik, Romain Cayrol, Hania Kébir, Chantale Auger, Monique Bernard, Alain Bouthillier, Robert Moumdjian, Pierre Duquette, Alexandre Prat*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

Objective: Dysregulation of the blood-brain barrier (BBB) and transendothelial migration of immune cells are among the earliest central nervous system changes partaking in lesion formation in both multiple sclerosis (MS) and its early clinical form, the clinically isolated syndrome. Evidence for the anti-inflammatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors within the central nervous system arose from studies demonstrating that statins improve clinical signs in the animal model of MS and reduce the number of gadolinium-enhancing lesions in MS. Methods: We sought to describe the impact of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor treatment on the physiology and immunology of human BBB-derived endothelial cells (ECs). Results: We demonstrate that lovastatin and simvastatin induce a 50 to 60% reduction in the diffusion rates of bovine serum albumin and [ 14C]-sucrose across human BBB-ECs in vitro through abrogation of isoprenylation processes, but independent of the expression of the tight junction molecules occludin, VE-cadherin, JAM-1, zonula occluden-1, and zonula occluden-2. Simvastatin and lovastatin were equipotent in reducing BBB permeability in vitro, with median effective concentration (EC 50) of 9.5 × 10 -8 and 1.0 × 10 -7M, respectively. We further demonstrate that lovastatin and simvastatin treatment of BBB-ECs significantly restricts the migration of clinically isolated syndrome-derived and MS-derived monocytes and lymphocytes across the human BBB in vitro, through a specific reduction in the secretion of the chemokines monocyte chemotactic protein-1/CCL2 and interferon-γ-inducible protein-10/CXCL10 by BBB-ECs. Interpretation: Our data parallel the previously reported magnetic resonance imaging-based radiological findings and suggest an effect of statins that could be beneficial in early MS, restricting the diffusion of molecular tracers and the migration of immune cells across the human BBB.

Original languageEnglish (US)
Pages (from-to)45-55
Number of pages11
JournalAnnals of neurology
Volume60
Issue number1
DOIs
StatePublished - Jul 2006

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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