Activated microglia/macrophages significantly contribute to the secondary inflammatory damage in ischemic stroke. Cultured neonatal microglia express the K þ channels Kv1.3 and KCa3.1, both of which have been reported to be involved in microglia-mediated neuronal killing, oxidative burst and cytokine production. However, it is questionable whether neonatal cultures accurately reflect the K þ channel expression of activated microglia in the adult brain. We here subjected mice to middle cerebral artery occlusion with eight days of reperfusion and patch-clamped acutely isolated microglia/macrophages. Microglia from the infarcted area exhibited higher densities of K þ currents with the biophysical and pharmacological properties of Kv1.3, KCa3.1 and Kir2.1 than microglia from non-infarcted control brains. Similarly, immunohistochemistry on human infarcts showed strong Kv1.3 and KCa3.1 immunoreactivity on activated microglia/ macrophages. We next investigated the effect of genetic deletion and pharmacological blockade of KCa3.1 in reversible middle cerebral artery occlusion. KCa3.1 À/À mice and wild-type mice treated with the KCa3.1 blocker TRAM-34 exhibited significantly smaller infarct areas on day-8 after middle cerebral artery occlusion and improved neurological deficit. Both manipulations reduced microglia/macrophage activation and brain cytokine levels. Our findings suggest KCa3.1 as a pharmacological target for ischemic stroke. Of potential, clinical relevance is that KCa3.1 blockade is still effective when initiated 12 h after the insult.

Introduction KCa2 or small-conductance Ca2+-activated K+ channels (SK) are expressed in many areas of the central nervous system where they participate in the regulation of neuronal afterhyperpolarization and excitability, and also serve as negative feedback regulators on the glutamate -NMDA pathway. Areas covered This review focuses on the role of KCa2 channels in learning and memory and their potential as therapeutic targets for Alzheimer’s and Parkinson’s disease, ataxia, schizophrenia, and alcohol dependence. Expert opinion There currently exists relatively solid evidence supporting the use of KCa2 activators for ataxia. Genetic KCa2 channel suppression in deep cerebellar neurons induces ataxia, while KCa2 activators like 1-EBIO, SKA-31 and NS13001 improve motor deficits in mouse models of episodic ataxia (EA) and spinal cerebellar ataxia (SCA). Use of KCa2 activators for ataxia is further supported by a report that riluzole improves ataxia in a small clinical trial. Based on accumulating literature evidence, KCa2 activators further appear attractive for the treatment of alcohol dependence and withdrawal. Regarding Alzheimer’s disease, Parkinson’s and schizophrenia further research, including long-term studies in disease relevant animal models, will be needed to determine whether KCa2 channels constitute valid targets and whether activators or inhibitors would be needed to positively affect disease outcomes.

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Activated microglia significantly contribute to the secondary inflammatory damage in ischemic stroke and therefore constitute attractive targets for post‐infarct intervention. Microglia express the voltage‐gated Kv1.3 and the calcium‐activated KCa3.1 channel and both channels are involved in microglia mediated neuronal killing, oxidative burst and inflammatory cytokine production. We previously found that KCa3.1 blockade with TRAM‐34 reduces neurological deficit and infarct area in a rat model of ischemic stroke even if initiated 12 hours after reperfusion. We now investigated whether Kv1.3 blockade would have similar effects and whether combined blockade of both microglial K+ channels would offer additional benefits. We subjected male Wistar rats to 90 min of middle cerebral artery occlusion (MCAO) and administered either vehicle or the Kv1.3 blocker PAP‐1 (40 mg/kg i.p. BID) for 7 days starting 12 h after reperfusion. PAP‐1 significantly reduced infarct area and improved neurological deficit in the infarcted hemisphere on day‐7. However, combined blockade of both Kv1.3 and KCa3.1 with PAP‐1 and TRAM‐34 did not further reduce infarct area compared to treatment with either TRAM‐34 or PAP‐1 alone suggesting that blockade of one microglial K+ channel is sufficient to improve outcomes of ischemic stroke.Supported by RO1 GM076063 from the National Institute of Health.