Neuroprotective effects of NMDA receptor glycine recognition site antagonism: dependence on glycine concentration.
High-affinity NMDA receptor glycine recognition site antagonists protect brain tissue from ischemic damage. The neuroprotective effect of 5-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021), a selective NMDA receptor antagonist with nanomolar affinity for the glycine binding site, was examined in rat cortical mixed neuronal/glial cultures. ACEA 1021 alone did not alter spontaneous lactate dehydrogenase (LDH) release. Treatment with ACEA 1021 (0.1-10 microM) before 500 microM glutamate, 30 microM NMDA, or 300 microM kainate exposure was found to reduce LDH release in a concentration-dependent fashion. These effects were altered by adding glycine to the medium. Glycine (1 mM) partially reversed the effect of ACEA 1021 on kainate cytotoxicity. Glycine (100 microM-1 mM) completely blocked the effects of ACEA 1021 on glutamate and NMDA cytotoxicity. The glycine concentration that produced a half-maximal potentiation of excitotoxin-induced LDH release in the presence of 1.0 microM ACEA 1021 was similar for glutamate and NMDA (18 +/- 3 and 29 +/- 9 microM, respectively). ACEA 1021 also reduced kainate toxicity in cultures treated with MK-801. The effects of glycine and ACEA 1021 on glutamate-induced LDH release were consistent with a model of simple competitive interaction for the strychnine-insensitive NMDA receptor glycine recognition site, although nonspecific effects at the kainate receptor may be of lesser importance.
Pearlstein
R D
RD
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Beirne
J P
JP
Massey
G W
GW
Warner
D S
DS
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism* / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009994:Osmolar Concentration; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats / Q000196:embryology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C092062:licostinel; D007770:L-Lactate Dehydrogenase; D007608:Kainic Acid; D005998:Glycine