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.

Blood–brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice

“…52,53 The dose, duration, and route of administration chosen for experiments in the current report were based on previous studies demonstrating restoration of BBB integrity in experimental autoimmune encephalitis after Enzastaurin treatment. 26 In vitro exposure to Enzastaurin upregulates tight junction proteins in murine cerebrovascular endothelial cells without altering basal or stimulated cytokine release. 26 Although the data in the current report do not conclusively demonstrate that systemic PKCb inhibition rescues hippocampal function by reestablishing BBB integrity, LTP deficits in db/db mice were unaffected by direct application of Enzastaurin.…”

“…26 In vitro exposure to Enzastaurin upregulates tight junction proteins in murine cerebrovascular endothelial cells without altering basal or stimulated cytokine release. 26 Although the data in the current report do not conclusively demonstrate that systemic PKCb inhibition rescues hippocampal function by reestablishing BBB integrity, LTP deficits in db/db mice were unaffected by direct application of Enzastaurin. This result suggests that restoration of synaptic plasticity and cognition with in vivo administration is unlikely to be centrally mediated.…”

“…25 Activation of protein kinase Cb (PKCb) increases BBB permeability and allows bone marrow-derived immune cells to enter the nervous system in models of infectious disease. 26 Diabetes also promotes PKCb-mediated cerebrovascular breakdown in the retina, 27 but mechanisms for BBB breakdown in the CNS remain to be determined, and the reported relationships between BBB breakdown, microglial activation, and cognitive deficits remain correlative at present. 4,5,28 We used the selective PKCb inhibitor LY-317615 (Enzastaurin) to re-seal the BBB in mice with genetic diabetes and obesity (db/db mice).…”

Protection of Tong-Qiao-Huo-Xue Decoction against Cerebral Ischemic Injury through Reduction Blood–Brain Barrier Permeability

“…4,5) These layered cell structures construct the so-called tight junction (TJ) and the TJ-associated protein of Claudin-5, Occludin and ZO-1, which contribute to the integrity of the BBB, and the changes of its composition and the expression of relative ingredients are closely associated with BBB permeability. [6][7][8] These proteins are the major structural protein of TJ, their expressions levels are relevant to the degree of cerebral microvascular permeability and cerebral edema.…”

Protein kinase C β inhibition by enzastaurin leads to mitotic missegregation and preferential cytotoxicity toward colorectal cancer cells with chromosomal instability (CIN)

“…6 Subsequent studies have expanded the role of PKC b to other vascular pathologies including tumor angiogenesis 7,8 and the disruption of the blood-brain barrier (BBB) in multiple sclerosis. 9 Increased PKC b signaling is implicated in different tumor types including colorectal cancer (CRC). Overexpression of PKC bII is accompanied by colonic hyperproliferation and increased sensitivity to colon carcinogenesis in transgenic mice 10,11 suggesting that activation of PKC bII is an early promotive event in colon carcinogenesis.…”