Acute or prolonged exposure to 1-aminocyclopropanecarboxylic acid protects spinal neurons against NMDA toxicity.
1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity partial agonist for the glycine binding site within the NMDA receptor complex. Chronic treatment with ACPC in vivo appears to reversibly desensitize the NMDA receptor complex, prompting suggestions that it might provide an effective means of ameliorating degenerative mechanisms mediated through this ligand-gated ion channel. In the present experiments, cultured rat spinal cord neurons were used to further examine the effects of acute and sustained ACPC exposures on N-methyl-D-aspartate (NMDA)-induced neurotoxicity. Cell damage was quantitatively assessed using a tetrazolium salt colorimetric assay. With coincubation, 1 mM ACPC significantly reduced the neuronal cell damage caused by 30 min exposure to 25 or 50 microM concentrations of NMDA, but, in contrast to other competitive and non-competitive NMDA receptor antagonists (D-(-)-2-amino-5-phosphonovaleric acid (APV), dizocilpine maleate (MK-801) and 7-chlorokynurenic acid (7-CK)), it failed to alter the cell injury induced by 100 microM NMDA. The protective effect of ACPC was competitively abolished by coaddition of glycine, verifying that it was mediated through glycine binding sites. Sustained 20 h exposure to 1 mM ACPC (which was removed 30 min before addition of 25 microM NMDA) also caused cells to be significantly less responsive to the neurotoxic effects of NMDA. Pre-exposure to ACPC for shorter intervals ( < 1 h) failed to alter subsequent NMDA toxicity. Acute or sustained exposures to ACPC alone did not affect cell viability. These results support earlier indications that: (1) ACPC provides an effective means of antagonizing excitotoxic phenomena, and (2) sustained exposure to ACPC desensitizes the NMDA receptor complex.
Lin
Y
Y
Division of Neurosciences, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Long
J B
JB
D000596:Amino Acids / Q000494:pharmacology*; D000598:Amino Acids, Cyclic; D000818:Animals; D002478:Cells, Cultured; D005998:Glycine / Q000494:pharmacology; D016202:N-Methylaspartate / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*
D000596:Amino Acids; D000598:Amino Acids, Cyclic; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; C023863:1-aminocyclopropane-1-carboxylic acid; D016202:N-Methylaspartate; D005998:Glycine