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Protein kinase C? 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 C?, 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 C? 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.

SUBMITTER: Lanz TV 

PROVIDER: S-EPMC3767524 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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

Lanz Tobias V TV   Becker Simon S   Osswald Matthias M   Bittner Stefan S   Schuhmann Michael K MK   Opitz Christiane A CA   Gaikwad Sadanand S   Wiestler Benedikt B   Litzenburger Ulrike M UM   Sahm Felix F   Ott Martina M   Iwantscheff Simeon S   Grabitz Carl C   Mittelbronn Michel M   von Deimling Andreas A   Winkler Frank F   Meuth Sven G SG   Wick Wolfgang W   Platten Michael M  

Proceedings of the National Academy of Sciences of the United States of America 20130819 36


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 mig  ...[more]

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