Chloride transport inhibitors influence recovery from oxygen-glucose deprivation-induced cellular injury in adult hippocampus

Neuropharmacology. 2004 Aug;47(2):253-62. doi: 10.1016/j.neuropharm.2004.04.002.

Abstract

Cerebral ischemia in vivo or oxygen-glucose deprivation (OGD) in vitro are characterized by major disturbances in neuronal ionic homeostasis, including significant rises in intracellular Na(+), Ca(2+), and Cl(-) and extracellular K(+). Recently, considerable attention has been focused on the cation-chloride cotransporters Na-K-Cl cotransporter isoform I (NKCC-1) and K-Cl cotransporter isoform II (KCC2), as they may play an important role in the disruption of ion gradients and subsequent ischemic damage. In this study, we examined the ability of cation-chloride transport inhibitors to influence the biochemical (i.e. ATP) and histological recovery of neurons in adult hippocampal slices exposed to OGD. In the hippocampus, 7 min of OGD caused a loss of ATP that recovered partially (approximately 50%) during 3 h of reoxygenation. Furosemide, which inhibits the NKCC-1 and KCC2 cotransporters, and bumetanide, a more specific NKCC-1 inhibitor, enhanced ATP recovery when measured 3 h after OGD. Furosemide and bumetanide also attenuated area CA1 neuronal injury after OGD. However, higher concentrations of these compounds appear to have additional non-specific toxic effects, limiting ATP recovery following OGD and promoting neuronal injury. The KCC2 cotransporter inhibitor DIOA and the Cl(-) ATPase inhibitor ethacrynic acid caused neuronal death even in the absence of OGD and promoted cytochrome c release from isolated mitochondria, indicating non-specific toxicities of these compounds.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Brain Ischemia / pathology
  • Bumetanide / pharmacology
  • Carrier Proteins / antagonists & inhibitors*
  • Cell Survival / drug effects
  • Chlorides / metabolism*
  • Cytochromes c / metabolism
  • Diuretics / pharmacology
  • Energy Metabolism / drug effects
  • Ethacrynic Acid / pharmacology
  • Furosemide / pharmacology
  • Glucose / deficiency*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology*
  • Hypoxia / pathology*
  • In Vitro Techniques
  • Male
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Potassium Chloride Symporter Inhibitors
  • Solute Carrier Family 12, Member 1
  • Solute Carrier Family 12, Member 2

Substances

  • Carrier Proteins
  • Chlorides
  • Diuretics
  • Slc12a1 protein, rat
  • Slc12a2 protein, rat
  • Sodium Potassium Chloride Symporter Inhibitors
  • Solute Carrier Family 12, Member 1
  • Solute Carrier Family 12, Member 2
  • Bumetanide
  • Furosemide
  • Adenosine Triphosphate
  • Cytochromes c
  • Glucose
  • Ethacrynic Acid