Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

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4 Citations (Scopus)

Abstract

Objective: Inhibitors of the voltage-gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up-regulated on "M1-like" microglia, we here tested the therapeutic hypothesis that the brain-penetrant small-molecule Kv1.3-inhibitor PAP-1 reduces secondary inflammatory damage after ischemia/reperfusion. Methods: We studied microglial Kv1.3 expression using electrophysiology and immunohistochemistry, and evaluated PAP-1 in hypoxia-exposed organotypic hippocampal slices and in middle cerebral artery occlusion (MCAO) with 8 days of reperfusion in both adult male C57BL/6J mice (60 min MCAO) and adult male Wistar rats (90 min MCAO). In both models, PAP-1 administration was started 12 h after reperfusion. Results: We observed Kv1.3 staining on activated microglia in ischemic infarcts in mice, rats, and humans and found higher Kv1.3 current densities in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of MCAO mice. PAP-1 reduced microglia activation and increased neuronal survival in hypoxia-exposed hippocampal slices as effectively as minocycline. In mouse MCAO, PAP-1 dose-dependently reduced infarct area, improved neurological deficit score, and reduced brain levels of IL-1β and IFN-γ without affecting IL-10 and brain-derived nerve growth factor (BDNF) levels or inhibiting ongoing phagocytosis. The beneficial effects on infarct area and neurological deficit score were reproduced in rats providing confirmation in a second species. Interpretation: Our findings suggest that Kv1.3 constitutes a promising therapeutic target for preferentially inhibiting "M1-like" inflammatory microglia/macrophage functions in ischemic stroke.

Original languageEnglish (US)
JournalAnnals of Clinical and Translational Neurology
DOIs
StateAccepted/In press - Jan 1 2017

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Kv1.3 Potassium Channel
Microglia
Infarction
Middle Cerebral Artery Infarction
Stroke
Inflammation
Reperfusion
Brain
Voltage-Gated Potassium Channels
Minocycline
Electrophysiology
Immunologic Factors
Nerve Growth Factor
Interleukin-1
Inbred C57BL Mouse
Phagocytosis
Interleukin-10
Autoimmune Diseases
Wistar Rats
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

Cite this

@article{b02149b4e717442ab61ae0d2e378e0a7,
title = "Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke",
abstract = "Objective: Inhibitors of the voltage-gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up-regulated on {"}M1-like{"} microglia, we here tested the therapeutic hypothesis that the brain-penetrant small-molecule Kv1.3-inhibitor PAP-1 reduces secondary inflammatory damage after ischemia/reperfusion. Methods: We studied microglial Kv1.3 expression using electrophysiology and immunohistochemistry, and evaluated PAP-1 in hypoxia-exposed organotypic hippocampal slices and in middle cerebral artery occlusion (MCAO) with 8 days of reperfusion in both adult male C57BL/6J mice (60 min MCAO) and adult male Wistar rats (90 min MCAO). In both models, PAP-1 administration was started 12 h after reperfusion. Results: We observed Kv1.3 staining on activated microglia in ischemic infarcts in mice, rats, and humans and found higher Kv1.3 current densities in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of MCAO mice. PAP-1 reduced microglia activation and increased neuronal survival in hypoxia-exposed hippocampal slices as effectively as minocycline. In mouse MCAO, PAP-1 dose-dependently reduced infarct area, improved neurological deficit score, and reduced brain levels of IL-1β and IFN-γ without affecting IL-10 and brain-derived nerve growth factor (BDNF) levels or inhibiting ongoing phagocytosis. The beneficial effects on infarct area and neurological deficit score were reproduced in rats providing confirmation in a second species. Interpretation: Our findings suggest that Kv1.3 constitutes a promising therapeutic target for preferentially inhibiting {"}M1-like{"} inflammatory microglia/macrophage functions in ischemic stroke.",
author = "Yi-Je Chen and Nguyen, {Hai M.} and Izumi Maezawa and Lee-Way Jin and Heike Wulff",
year = "2017",
month = "1",
day = "1",
doi = "10.1002/acn3.513",
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TY - JOUR

T1 - Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

AU - Chen, Yi-Je

AU - Nguyen, Hai M.

AU - Maezawa, Izumi

AU - Jin, Lee-Way

AU - Wulff, Heike

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Objective: Inhibitors of the voltage-gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up-regulated on "M1-like" microglia, we here tested the therapeutic hypothesis that the brain-penetrant small-molecule Kv1.3-inhibitor PAP-1 reduces secondary inflammatory damage after ischemia/reperfusion. Methods: We studied microglial Kv1.3 expression using electrophysiology and immunohistochemistry, and evaluated PAP-1 in hypoxia-exposed organotypic hippocampal slices and in middle cerebral artery occlusion (MCAO) with 8 days of reperfusion in both adult male C57BL/6J mice (60 min MCAO) and adult male Wistar rats (90 min MCAO). In both models, PAP-1 administration was started 12 h after reperfusion. Results: We observed Kv1.3 staining on activated microglia in ischemic infarcts in mice, rats, and humans and found higher Kv1.3 current densities in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of MCAO mice. PAP-1 reduced microglia activation and increased neuronal survival in hypoxia-exposed hippocampal slices as effectively as minocycline. In mouse MCAO, PAP-1 dose-dependently reduced infarct area, improved neurological deficit score, and reduced brain levels of IL-1β and IFN-γ without affecting IL-10 and brain-derived nerve growth factor (BDNF) levels or inhibiting ongoing phagocytosis. The beneficial effects on infarct area and neurological deficit score were reproduced in rats providing confirmation in a second species. Interpretation: Our findings suggest that Kv1.3 constitutes a promising therapeutic target for preferentially inhibiting "M1-like" inflammatory microglia/macrophage functions in ischemic stroke.

AB - Objective: Inhibitors of the voltage-gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up-regulated on "M1-like" microglia, we here tested the therapeutic hypothesis that the brain-penetrant small-molecule Kv1.3-inhibitor PAP-1 reduces secondary inflammatory damage after ischemia/reperfusion. Methods: We studied microglial Kv1.3 expression using electrophysiology and immunohistochemistry, and evaluated PAP-1 in hypoxia-exposed organotypic hippocampal slices and in middle cerebral artery occlusion (MCAO) with 8 days of reperfusion in both adult male C57BL/6J mice (60 min MCAO) and adult male Wistar rats (90 min MCAO). In both models, PAP-1 administration was started 12 h after reperfusion. Results: We observed Kv1.3 staining on activated microglia in ischemic infarcts in mice, rats, and humans and found higher Kv1.3 current densities in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of MCAO mice. PAP-1 reduced microglia activation and increased neuronal survival in hypoxia-exposed hippocampal slices as effectively as minocycline. In mouse MCAO, PAP-1 dose-dependently reduced infarct area, improved neurological deficit score, and reduced brain levels of IL-1β and IFN-γ without affecting IL-10 and brain-derived nerve growth factor (BDNF) levels or inhibiting ongoing phagocytosis. The beneficial effects on infarct area and neurological deficit score were reproduced in rats providing confirmation in a second species. Interpretation: Our findings suggest that Kv1.3 constitutes a promising therapeutic target for preferentially inhibiting "M1-like" inflammatory microglia/macrophage functions in ischemic stroke.

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