title: Blockade of Kv1.3 channels ameliorates radiation-induced brain injury.
abstract: BACKGROUND
  Tumors affecting the head, neck, and brain account for significant morbidity and mortality. The curative efficacy of radiotherapy for these tumors is well established, but radiation carries a significant risk of neurologic injury. So far, neuroprotective therapies for radiation-induced brain injury are still limited. In this study we demonstrate that Stichodactyla helianthus (ShK)-170, a specific inhibitor of the voltage-gated potassium (Kv)1.3 channel, protected mice from radiation-induced brain injury.
  
  
  METHODS
  Mice were treated with ShK-170 for 3 days immediately after brain irradiation. Radiation-induced brain injury was assessed by MRI scans and a Morris water maze. Pathophysiological change of the brain was measured by immunofluorescence. Gene and protein expressions of Kv1.3 and inflammatory factors were measured by quantitative real-time PCR, reverse transcription PCR, ELISA assay, and western blot analyses. Kv currents were recorded in the whole-cell configuration of the patch-clamp technique.
  
  
  RESULTS
  Radiation increased Kv1.3 mRNA and protein expression in microglia. Genetic silencing of Kv1.3 by specific short interference RNAs or pharmacological blockade with ShK-170 suppressed radiation-induced production of the proinflammatory factors interleukin-6, cyclooxygenase-2, and tumor necrosis factor-α by microglia. ShK-170 also inhibited neurotoxicity mediated by radiation-activated microglia and promoted neurogenesis by increasing the proliferation of neural progenitor cells.
  
  
  CONCLUSIONS
  The therapeutic effect of ShK-170 is mediated by suppression of microglial activation and microglia-mediated neurotoxicity and enhanced neurorestoration by promoting proliferation of neural progenitor cells.
authors.affiliation: Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China (Y.P., K.L., Z.L., Y.W., B.H., P.X., X.S., Y.T.); Department of Neurosurgery, Shanghai 10th People's Hospital, Tongji University, Shanghai, China (Y.Z., B.Z.); Peptides International, Louisville, Kentucky (M.P.); Department of Physiology and Biophysics, University of California, Irvine, Irvine, California (K.G.C.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.forename: Kui
authors.initials: K
authors.lastname: Lu
authors.forename: Zichen
authors.initials: Z
authors.lastname: Li
authors.forename: Yaodong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Pengfei
authors.initials: P
authors.lastname: Xu
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Shi
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Michael
authors.initials: M
authors.lastname: Pennington
authors.forename: K George
authors.initials: KG
authors.lastname: Chandy
authors.forename: Yamei
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D001930:Brain Injuries / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003064:Cnidarian Venoms / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D011832:Radiation Injuries / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D003064:Cnidarian Venoms; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C095391:ShK neurotoxin
keywords: Kv1.3; ShK; microglia; radiation