title: The potassium channel KCa3.1 constitutes a pharmacological target for neuroinflammation associated with ischemia/reperfusion stroke.
abstract: Activated microglia/macrophages significantly contribute to the secondary inflammatory damage in ischemic stroke. Cultured neonatal microglia express the K+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+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+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-/-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.
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA.|Microsurgery Core, University of California, Davis, CA, USA.
authors.forename: Yi-Je
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA.
authors.forename: Hai M
authors.initials: HM
authors.lastname: Nguyen
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA.|M.I.N.D. Institute, University of California, Davis, Sacramento, CA, USA.
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Grössinger
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA.
authors.forename: April L
authors.initials: AL
authors.lastname: Garing
authors.affiliation: Aragon Institute of Health Sciences/IIS and ARAID, Zaragoza, Spain.
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA.|M.I.N.D. Institute, University of California, Davis, Sacramento, CA, USA.
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA hwulff@ucdavis.edu.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors*; D008262:Macrophage Activation; D051379:Mice; D058990:Molecular Targeted Therapy; D020078:Neurogenic Inflammation / Q000188:drug therapy*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D020521:Stroke / Q000473:pathology*
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D011720:Pyrazoles; C411671:TRAM 34
keywords: KCa3.1; TRAM-34; microglia activation; middle cerebral artery occlusion; potassium channel