Glycine-induced neurotoxicity in organotypic hippocampal slice cultures

Exp Brain Res. 2005 Mar;161(3):351-7. doi: 10.1007/s00221-004-2079-7. Epub 2004 Oct 14.

Abstract

The role of the neutral amino acid glycine in excitotoxic neuronal injury is unclear. Glycine coactivates glutamate N-methyl-D-aspartate (NMDA) receptors by binding to a distinct recognition site on the NR1 subunit. Purely excitatory glycine receptors composed of NR1 and NR3/NR4 NMDA receptor subunits have recently been described, raising the possibility of excitotoxic effects mediated by glycine alone. We have previously shown that exposure to high concentrations of glycine causes extensive neurotoxicity in organotypic hippocampal slice cultures by activation of NMDA receptors. In the present study, we investigated further properties of in vitro glycine-mediated toxicity. Agonists of the glycine recognition site of NMDA receptors (D-serine and D-alanine) did not have any toxic effect in hippocampal cultures, whereas competitive blockade of the glycine site by 7-chlorokynurenic acid was neuroprotective. Stimulation (taurine, beta-alanine) or inhibition (strychnine) of the inhibitory strychnine-sensitive glycine receptors did not produce any neurotoxicity. The toxic effects of high-dose glycine were comparable in extent to those produced by the excitatory amino acid glutamate in our model. When combined with sublethal hypoxia/hypoglycemia, the threshold of glycine toxicity was decreased to less than 1 mM, which corresponds to the range of concentrations of excitatory amino acids measured during in vivo cerebral ischemia. Taken together, these results further support the assumption of an active role of glycine in excitotoxic neuronal injury.

MeSH terms

  • Alanine / pharmacology
  • Animals
  • Animals, Newborn
  • Brain Ischemia / metabolism
  • Brain Ischemia / physiopathology
  • Dose-Response Relationship, Drug
  • Drug Resistance / physiology
  • Glutamic Acid / toxicity
  • Glycine / toxicity*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Kynurenic Acid / analogs & derivatives
  • Kynurenic Acid / pharmacology
  • Nerve Degeneration / chemically induced*
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / physiopathology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Neurotoxins / toxicity*
  • Organ Culture Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Strychnine / pharmacology
  • Taurine / pharmacology

Substances

  • Neuroprotective Agents
  • Neurotoxins
  • Receptors, N-Methyl-D-Aspartate
  • Taurine
  • Glutamic Acid
  • Kynurenic Acid
  • Strychnine
  • Alanine
  • 7-chlorokynurenic acid
  • Glycine