Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis.
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 [(14)C]-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 x 10(-8) and 1.0 x 10(-7)M, 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-gamma-inducible protein-10/CXCL10 by BBB-ECs.


CONCLUSIONS
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.
Ifergan
Igal
I
Neuroimmunology Laboratory, Center for Research on Brain Diseases, Centre Hospitalier de l'Université de Montreal, CHUM Research Center, Quebec, Canada.
Wosik
Karolina
K
Cayrol
Romain
R
Kébir
Hania
H
Auger
Chantale
C
Bernard
Monique
M
Bouthillier
Alain
A
Moumdjian
Robert
R
Duquette
Pierre
P
Prat
Alexandre
A
D000328:Adult; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D017368:Protein Prenylation; D019821:Simvastatin / Q000494:pharmacology*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
C111835:CCL2 protein, human; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D008148:Lovastatin; D019821:Simvastatin