The Kv1.3 Blocker PAP‐1 Reduces Infarction and Neurological Deficit in a Rat Model of Reperfusion Stroke

Abstract

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.