Protein kinase Cβ as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis.

Abstract

Disruption of the blood-brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase Cβ, which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase Cβ in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS.

• Authors: Tobias V Lanz, Simon Becker, Matthias Osswald, Stefan Bittner, Michael K Schuhmann, Christiane A Opitz, Sadanand Gaikwad, Benedikt Wiestler, Ulrike M Litzenburger, Felix Sahm, Martina Ott, Simeon Iwantscheff, Carl Grabitz, Michel Mittelbronn, Andreas von Deimling, Frank Winkler, Sven G Meuth, Wolfgang Wick, Michael Platten
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 36 Pg. 14735-40 (Sep 03 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23959874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Claudin-3
• Claudin-5
• Cytokines
• Indoles
• Zonula Occludens-1 Protein
• Protein Kinase C beta
• enzastaurin

Topics

• Animals
• Blood-Brain Barrier (drug effects, immunology)
• Cell Proliferation (drug effects)
• Claudin-3 (immunology, metabolism)
• Claudin-5 (immunology, metabolism)
• Cytokines (immunology, metabolism)
• Demyelinating Diseases (immunology, prevention & control)
• Dose-Response Relationship, Drug
• Encephalomyelitis, Autoimmune, Experimental (immunology, pathology, prevention & control)
• Endothelial Cells (drug effects, immunology, metabolism)
• Female
• Gene Expression Profiling
• Immunohistochemistry
• Indoles (immunology, pharmacology)
• Inflammation (immunology, metabolism, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred Strains
• Microscopy, Confocal
• Protein Kinase C beta (antagonists & inhibitors, immunology, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes (drug effects, immunology, metabolism)
• Tight Junctions (drug effects, immunology, metabolism)
• Transendothelial and Transepithelial Migration (drug effects, immunology)
• Zonula Occludens-1 Protein (immunology, metabolism)