The Voltage-Gated Potassium Channel Kv1.3 as a Target for Inhibiting Detrimental M1 Microglia Functions

Abstract

Kv1.3 was first discovered in human T cells in 1984 and has since then been pursued as a potential target for immunosuppression. It was later shown to be overexpressed in effector memory T cells, suggesting that Kv1.3 blockers would be particularly useful for the treatment of T cell mediated autoimmune diseases like multiple sclerosis, psoriasis and rheumatoid arthritis. In fact, the Kv1.3 blocking peptide ShK-186 has recently been found to be effective in Phase-1b study for psoriatic arthritis. We hypothesized that Kv1.3 blockers might also be useful for reducing microglia activation in ischemic stroke and other neurological diseases accompanied by neuroinflammation. Starting with cultured microglia, we observed that Kv1.3 expression is up-regulated in pro-inflammatory M1-like microglia and that Kv1.3 blockers preferentially reduce the production of IL-1beta and TNF-alpha without affecting IL-10 production. In organotypic hippocampal slices exposed to hypoxia/aglycemia Kv1.3 blockers significantly reduced microglia activation and increased neuronal survival. We further observed strong Kv1.3 expression on iNOS expressing inflammatory microglia in human stroke biopsies validating Kv1.3 as potential target. In both mouse and rat models of ischemic stroke the small molecule Kv1.3 blocker PAP-1 significantly reduced infarct area and improved neurological deficit 7 days after reperfusion when administered 12 hours after reperfusion. In the mouse model, PAP-1 selectively reduced brain levels of the inflammatory cytokines IL1-beta and IFN-gamma without affecting IL-10 and BDNF. Based on these findings we propose Kv1.3 inhibitors as potential therapeutic agents for preferentially inhibiting pro-inflammatory M1 microglia functions in ischemic stroke and other neurological diseases.Supported by GM076063 and AG043788.