Preconditioning induces tolerance by suppressing glutamate release in neuron culture ischemia models

J Neurochem. 2012 Jul;122(2):470-81. doi: 10.1111/j.1471-4159.2012.07791.x. Epub 2012 Jun 1.


This study determined how preconditioned neurons responded to oxygen-glucose deprivation (OGD) to result in neuroprotection instead of neurotoxicity. Neurons preconditioned using chronically elevated synaptic activity displayed suppressed elevations in extracellular glutamate ([glutamateex ]) and intracellular Ca(2+) (Ca(2+) in ) during OGD. The glutamate uptake inhibitor TBOA induced neurotoxicity, but at a longer OGD duration for preconditioned cultures, suggestive of delayed up-regulation of transporter activity relative to non-preconditioned cultures. This delay was attributed to a critically attenuated release of glutamate, based on tolerance observed against insults mimicking key neurotoxic signaling during OGD (OGD-mimetics). Specifically, in the presence of TBOA, preconditioned neurons displayed potent protection to the OGD-mimetics: ouabain (a Na(+) /K(+) ATPase inhibitor), high 55 mM KCl extracellular buffer (plasma membrane depolarization), veratridine (a Na(+) ionophore), and paraquat (intracellular superoxide producer), which correlated with suppressed [glutamateex ] elevations in the former two insults. Tolerance by preconditioning was reversed by manipulations that increased [glutamateex ], such as by exposure to TBOA or GABAA receptor agonists during OGD, or by exposure to exogenous NMDA or glutamate. Pre-synaptic suppression of neuronal glutamate release by preconditioning, possibly via suppressed exocytic release, represents a key convergence point in neuroprotection during exposure to OGD and OGD-mimetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Signaling / physiology
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / physiology
  • Cell Size
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Transporter 2 / antagonists & inhibitors
  • Female
  • Glucose / deficiency
  • Glutamic Acid / metabolism*
  • Ischemia / metabolism
  • Ischemia / pathology*
  • Ischemic Preconditioning / methods*
  • Neurons / metabolism*
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species
  • Receptors, GABA / drug effects
  • Receptors, Presynaptic / drug effects
  • Sodium / metabolism
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Vesicular Glutamate Transport Proteins / metabolism
  • Zinc / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • Excitatory Amino Acid Transporter 2
  • Reactive Oxygen Species
  • Receptors, GABA
  • Receptors, Presynaptic
  • Slc1a2 protein, rat
  • Vesicular Glutamate Transport Proteins
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Sodium
  • Sodium-Potassium-Exchanging ATPase
  • Glucose
  • Zinc
  • Calcium