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

Annals of Clinical and Translational Neurology
Yi-Je ChenHeike Wulff

Abstract

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. 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. 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...Continue Reading

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Citations

Jun 4, 2019·Journal of Neuroinflammation·Tianwen GaoSrikant Rangaraju
Dec 14, 2018·Frontiers in Cellular Neuroscience·Starlee LivelyLyanne C Schlichter
Jul 1, 2020·The Journal of Clinical Investigation·Souvarish SarkarAnumantha G Kanthasamy
Mar 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Supriya RameshaSrikant Rangaraju
Mar 4, 2021·Nature Reviews. Cardiology·Jana GruneMatthias Nahrendorf
Jul 13, 2020·Biochemical Pharmacology·Gabor TajtiRaymond S Norton
Apr 4, 2021·Journal of Clinical Medicine·Alexandru CojocaruEugen Osiac
Apr 20, 2021·Platelets·Joy R Wright, Martyn P Mahaut-Smith
May 2, 2021·Medicinal Research Reviews·Špela GubičLucija P Mašič
Jun 15, 2021·Frontiers in Aging Neuroscience·Sarah SaxenaMervyn Maze
Oct 8, 2021·Annals of Clinical and Translational Neurology·Yi-Je ChenHeike Wulff

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Methods Mentioned

BETA
xenograft
flow cytometry
biopsy
Assay

Software Mentioned

Origin
Image J

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