Treatment with the KCa3.1 inhibitor TRAM-34 during diabetic ketoacidosis reduces inflammatory changes in the brain

Nicole Glaser, Christopher Little, Weei Lo, Michael Cohen, Daniel J Tancredi, Heike Wulff, Martha E O'Donnell

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6 Citations (Scopus)

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: Inhibiting KCa3.1 activity with TRAM-34 during DKA treatment decreases microglial activation and reduces reactive astrogliosis, suggesting a decreased inflammatory response.

Original languageEnglish (US)
JournalPediatric Diabetes
DOIs
StateAccepted/In press - 2016

Fingerprint

Diabetic Ketoacidosis
Brain
Glial Fibrillary Acidic Protein
Bumetanide
Therapeutics
Brain Injuries
Hippocampus
Sodium-Potassium-Chloride Symporters
Staining and Labeling
TRAM 34
Brain Edema
Microglia
Ischemia
Immunohistochemistry
Insulin

Keywords

  • Bumetanide
  • Cerebral edema
  • Cerebral injury
  • Diabetic ketoacidosis
  • TRAM-34

ASJC Scopus subject areas

  • Internal Medicine
  • Pediatrics, Perinatology, and Child Health
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{5fd9393e36a1442fa1bfbb1d3775d273,
title = "Treatment with the KCa3.1 inhibitor TRAM-34 during diabetic ketoacidosis reduces inflammatory changes in the brain",
abstract = "Background: 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. Methods: 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. Results: 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. Conclusions: Inhibiting KCa3.1 activity with TRAM-34 during DKA treatment decreases microglial activation and reduces reactive astrogliosis, suggesting a decreased inflammatory response.",
keywords = "Bumetanide, Cerebral edema, Cerebral injury, Diabetic ketoacidosis, TRAM-34",
author = "Nicole Glaser and Christopher Little and Weei Lo and Michael Cohen and Tancredi, {Daniel J} and Heike Wulff and O'Donnell, {Martha E}",
year = "2016",
doi = "10.1111/pedi.12396",
language = "English (US)",
journal = "Pediatric Diabetes",
issn = "1399-543X",
publisher = "Blackwell Munksgaard",

}

TY - JOUR

T1 - Treatment with the KCa3.1 inhibitor TRAM-34 during diabetic ketoacidosis reduces inflammatory changes in the brain

AU - Glaser, Nicole

AU - Little, Christopher

AU - Lo, Weei

AU - Cohen, Michael

AU - Tancredi, Daniel J

AU - Wulff, Heike

AU - O'Donnell, Martha E

PY - 2016

Y1 - 2016

N2 - Background: 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. Methods: 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. Results: 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. Conclusions: Inhibiting KCa3.1 activity with TRAM-34 during DKA treatment decreases microglial activation and reduces reactive astrogliosis, suggesting a decreased inflammatory response.

AB - Background: 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. Methods: 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. Results: 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. Conclusions: Inhibiting KCa3.1 activity with TRAM-34 during DKA treatment decreases microglial activation and reduces reactive astrogliosis, suggesting a decreased inflammatory response.

KW - Bumetanide

KW - Cerebral edema

KW - Cerebral injury

KW - Diabetic ketoacidosis

KW - TRAM-34

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U2 - 10.1111/pedi.12396

DO - 10.1111/pedi.12396

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SN - 1399-543X

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