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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/6 J  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 ‐1 β  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.

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