title: Treatment with the KCa3.1 inhibitor TRAM-34 during diabetic ketoacidosis reduces inflammatory changes in the brain.
abstract: Diabetic ketoacidosis (DKA) causes brain injuries in children ranging from subtle to life-threatening. Previous studies suggest that DKA-related brain injury may involve both stimulation of Na-K-Cl cotransport and microglial activation. Other studies implicate the Na-K-Cl cotransporter and the Ca-activated K channel KCa3.1 in activation of microglia and ischemia-induced brain edema. In this study, we determined whether inhibiting cerebral Na-K-Cl cotransport or KCa3.1 could reduce microglial activation and decrease DKA-related inflammatory changes in the brain.
  
  
  
  Using immunohistochemistry, we investigated cellular alterations in brain specimens from juvenile rats with DKA before, during and after insulin and saline treatment. We compared findings in rats treated with and without bumetanide (an inhibitor of Na-K-Cl cotransport) or the KCa3.1 inhibitor TRAM-34.
  
  
  
  Glial fibrillary acidic protein (GFAP) staining intensity was increased in the hippocampus during DKA, suggesting reactive astrogliosis. OX42 staining intensity was increased during DKA in the hippocampus, cortex and striatum, indicating microglial activation. Treatment with TRAM-34 decreased both OX42 and GFAP intensity suggesting a decreased inflammatory response to DKA. Treatment with bumetanide did not significantly alter OX42 or GFAP intensity.
  
  
  
  Inhibiting KCa3.1 activity with TRAM-34 during DKA treatment decreases microglial activation and reduces reactive astrogliosis, suggesting a decreased inflammatory response.
authors.affiliation: Department of Pediatrics, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Glaser
authors.affiliation: Department of Pediatrics, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Little
authors.affiliation: Department of Pediatrics, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Weei
authors.initials: W
authors.lastname: Lo
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen
authors.affiliation: Department of Pediatrics, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tancredi
authors.affiliation: Department of Pharmacology, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002034:Bumetanide / Q000627:therapeutic use; D039481:CD11b Antigen / Q000037:antagonists & inhibitors / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016883:Diabetic Ketoacidosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004660:Encephalitis / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D005911:Gliosis / Q000209:etiology / Q000517:prevention & control; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011897:Random Allocation; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D039481:CD11b Antigen; C000614142:Gfap protein, rat; D005904:Glial Fibrillary Acidic Protein; C496901:Kcnn3 protein, rat; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D051640:Small-Conductance Calcium-Activated Potassium Channels; D049994:Sodium Potassium Chloride Symporter Inhibitors; C411671:TRAM 34; D002034:Bumetanide
keywords: TRAM-34; bumetanide; cerebral edema; cerebral injury; diabetic ketoacidosis