The inhibitory mGluR agonist, S-4-carboxy-3-hydroxy-phenylglycine selectively attenuates NMDA neurotoxicity and oxygen-glucose deprivation-induced neuronal death

Neuropharmacology. 1995 Aug;34(8):1081-7. doi: 10.1016/0028-3908(95)00073-f.


We examined the effect of two novel phenylglycine derivative drugs on excitotoxicity in murine cortical cell cultures: S-4-carboxy-3-hydroxy-phenylglycine (4C3HPG), a selective agonist of mGluRs 2/3 and an antagonist at mGluRs 1/5, and S-3 hydroxy-phenylglycine (3HPG), an agonist of mGluRs 1/5. 4C3HPG attenuated slowly-triggered NMDA-induced excitotoxic neuronal death, as well as the death induced by combined oxygen-glucose deprivation, but did not affect slowly-triggered excitotoxicity induced by AMPA or kainate. As expected, 4C3HPG also reduced NMDA-induced increases in cAMP in near-pure neuronal cultures, and the protective effect of 4C3HPG on NMDA toxicity could be reversed by adding 8-(4-chlorophenylthio)-adenosine 3':5'-cyclic-monophosphate (CPT cAMP) to the exposure medium. In contrast, 3HPG did not did not have any protective effects in these paradigms; in fact, slowly-triggered NMDA-induced excitotoxicity and the neuronal cell death induced by oxygen-glucose deprivation were potentiated. These results are consistent with the idea that the "inhibitory" mGluRs 2/3 exert a negative modulatory action on NMDA receptor-mediated excitotoxicity via reduction in neuronal cAMP levels.

MeSH terms

  • Animals
  • Cell Hypoxia / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Culture Media
  • Cyclic AMP / biosynthesis
  • Excitatory Amino Acid Agonists / pharmacology*
  • Glucose / deficiency*
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • N-Methylaspartate / antagonists & inhibitors*
  • N-Methylaspartate / toxicity
  • Neurons / drug effects*
  • Neurons / metabolism
  • Rats
  • Receptors, Metabotropic Glutamate / agonists*


  • Culture Media
  • Excitatory Amino Acid Agonists
  • Receptors, Metabotropic Glutamate
  • 4-carboxy-3-hydroxyphenylglycine
  • N-Methylaspartate
  • 4-hydroxyphenylglycine
  • Cyclic AMP
  • Glucose
  • Glycine