The inhibitory mGluR agonist, S-4-carboxy-3-hydroxy-phenylglycine selectively attenuates NMDA neurotoxicity and oxygen-glucose deprivation-induced neuronal death.
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.
Center for the Study of Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA.
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Buisson
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Choi
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D003470:Culture Media; D000242:Cyclic AMP / Q000096:biosynthesis; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*
D003470:Culture Media; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C078245:4-carboxy-3-hydroxyphenylglycine; D016202:N-Methylaspartate; C023010:4-hydroxyphenylglycine; D000242:Cyclic AMP; D005947:Glucose; D005998:Glycine