title: 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: German Cancer Consortium (DKTK) Clinical Cooperation Units Neuroimmunology and Brain Tumor Immunology, Neurooncology, and Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors: Tobias V
authors: TV
authors: Lanz
authors: Simon
authors: S
authors: Becker
authors: Matthias
authors: M
authors: Osswald
authors: Stefan
authors: S
authors: Bittner
authors: Michael K
authors: MK
authors: Schuhmann
authors: Christiane A
authors: CA
authors: Opitz
authors: Sadanand
authors: S
authors: Gaikwad
authors: Benedikt
authors: B
authors: Wiestler
authors: Ulrike M
authors: UM
authors: Litzenburger
authors: Felix
authors: F
authors: Sahm
authors: Martina
authors: M
authors: Ott
authors: Simeon
authors: S
authors: Iwantscheff
authors: Carl
authors: C
authors: Grabitz
authors: Michel
authors: M
authors: Mittelbronn
authors: Andreas
authors: A
authors: von Deimling
authors: Frank
authors: F
authors: Winkler
authors: Sven G
authors: SG
authors: Meuth
authors: Wolfgang
authors: W
authors: Wick
authors: Michael
authors: M
authors: Platten
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D062465:Claudin-3 / Q000276:immunology / Q000378:metabolism; D062507:Claudin-5 / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003711:Demyelinating Diseases / Q000276:immunology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D007211:Indoles / Q000276:immunology / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018613:Microscopy, Confocal; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000276:immunology; D062826:Zonula Occludens-1 Protein / Q000276:immunology / Q000378:metabolism
chemical_list: D062465:Claudin-3; D062507:Claudin-5; D016207:Cytokines; D007211:Indoles; D062826:Zonula Occludens-1 Protein; D064546:Protein Kinase C beta; C504878:enzastaurin
keywords: CNS; EAE; enzastaurin
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