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Kv1.3 Constitutes a Valid Target for Reducing Neuroinflammation in the Wake of Ischemic Stroke in Male, Female and Aged Mice
Author(s) -
Chen Yi-Je,
Nguyen Hai M.,
Cui Yanjun,
Wulff Heike
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03005
Subject(s) - microglia , cx3cr1 , neuroinflammation , medicine , stroke (engine) , immunofluorescence , endocrinology , patch clamp , inflammation , immunology , receptor , chemokine , antibody , mechanical engineering , chemokine receptor , engineering
The voltage‐gated Kv1.3 channel was first discovered in human T cells in 1984 and has since then been pursued as a target for autoimmune diseases. Kv1.3 is further expressed on pro‐inflammatory microglia and our laboratory therefore evaluated the small molecule Kv1.3 blocker PAP‐1 in models of ischemic stroke. In both male C57BL/6J mice and male Wistar rats, treatment with PAP‐1 started 12 hours after reperfusion reduced infarction and inflammatory brain cytokine levels and improved neurological deficit on day‐8 after reperfusion MCAO (Y.‐J. Chen et al. 2018). In order to test the therapeutic hypothesis that Kv1.3 inhibition is equally effective in both sexes, we established 60‐min MCAO with reperfusion in female C57BL/6J mice. Females have smaller infarcts, but 4‐months old animals of both sexes showed qualitatively similar pathologies with similar IBA + ‐microglia/macrophage and T cell densities and a GFAP + glial scar. Based on patch‐clamp recordings performed on acutely isolated CD11 + cells Cx3cr1 GFP/+ male and female mice exhibit similar Kv1.3 current densities on microglia/macrophages from the infarcted area. Immunofluorescence revealed that in both male and female Cx3cr1 GFP/+ mice Kv1.3 expression increases with time after MCAO, peaks around day‐7 and is localized to GFP + microglia/macrophages and CD3 + T cells. Since these findings suggest that both sexes would equally benefit from Kv1.3 inhibition, we subjected 4‐month and 20‐month old male and female WT and Kv1.3 −/− mice to 60 min‐MCAO with reperfusion. T2‐weigthed MRI revealed that Kv1.3‐deletion produces a significant reduction in infarct volume on day‐8 in both sexes. The reduction in infarction was most effective in aged Kv1.3 −/− females. Based on these observations and the finding that treatment with PAP‐1 significantly reduces infarction in 4‐months old WT female mice (n=14), we conclude that Kv1.3 inhibition effectively reduces stroke associated inflammation in both sexes independent of age. Support or Funding Information Supported by NIH (NS100294).