Abstract
BackgroundDisruption of blood–brain barrier (BBB) and subsequent infiltration of auto-reactive T lymphocytes are major characteristics of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Kv1.3 channel blockers are demonstrated potential therapeutic effects on MS patients and EAE models, maybe via reducing activation of T cells. However, it remains to be explored whether Kv1.3 channel blockers maintain integrity of BBB in MS model.ResultsIn this study, ImKTx88, a highly selective Kv1.3 channel blocker, was used to determine the role of Kv1.3 channel in the pathogenesis of EAE, particularly in the maintenance of BBB. ImKTx88 ameliorated pathological severity in the EAE rats, and reduced extravasation into CNS. ImKTx88 also ameliorated the severity of loss or redistribution of tight junction proteins, and inhibited over-expression of ICAM-1 and VCAM-1 in the brain from EAE rats. Furthermore ImKTx88 protection was associated with activation of Ang-1/Tie-2 axis, and might be due to decreased IL-17 production.ConclusionsImKTx88 may be a novel therapeutic agent for MS treatment by stabilizing the BBB.
Highlights
Disruption of blood–brain barrier (BBB) and subsequent infiltration of auto-reactive T lymphocytes are major characteristics of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE)
Because cerebellum is a main inflamed area in the EAE rat brain [25], histopathology of cerebellum were employed to assess the severity of EAE using hematoxylin–eosin (HE) and Luxol fast blue (LFB) staining
In this study, we demonstrate that the selective Kv1.3 channel blocker ImKTx88 has a therapeutic effect on EAE via protecting BBB, which was associated with the activation of the Ang-1/tyrosine kinase 2 (Tie-2) axis and reduced activation of Kv1.3high Th17 cells
Summary
Disruption of blood–brain barrier (BBB) and subsequent infiltration of auto-reactive T lymphocytes are major characteristics of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Kv1.3 channel blockers are demonstrated potential therapeutic effects on MS patients and EAE models, maybe via reducing activation of T cells. It remains to be explored whether Kv1.3 channel blockers maintain integrity of BBB in MS model. Multiple sclerosis (MS) is a typical neuroinflammatory demyelinating disease characterized by breakdown of blood–brain barrier (BBB) and infiltration of activated myelin-reactive T cells into the parenchyma of the central nervous system (CNS) [1]. Angiopoietin-1 (Ang-1), one of angiopoietins derived from perivascular cells, binds to the endothelial-specific receptor tyrosine kinase 2 (Tie-2) for maintaining
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