ACUTE OR PROLONGED EXPOSURE TO 1-AMINOCYCLOPROPANECARBOXYLIC ACID PROTECTS SPINAL NEURONS AGAINST NMDA TOXICITY

1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity partial a gonist 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 t hrough this Ligand-gated ion channel. In the present experiments, cult ured rat spinal cord neurons were used to further examine the effects of acute and sustained ACPC exposures on N-methyl-D-aspartate (NMDA)-i nduced neurotoxicity. Cell damage was quantitatively assessed using a tetrazolium salt colorimetric assay. With coincubation, 1 mM ACPC sign ificantly reduced the neuronal cell damage caused by 30 min exposure t o 25 or 50 mu M concentrations of NMDA, but, in contrast to other comp etitive and non-competitive NMDA receptor antagonists (D-(-)-2-amino-5 -phosphonovaleric acid (APV), dizocilpine maleate (MK-801) and 7-chlor okynurenic acid (7-CK)), it failed to alter the cell injury induced by 100 mu M NMDA. The protective effect of ACPC was competitively abolis hed by coaddition of glycine, verifying that it was mediated through g lycine binding sites. Sustained 20 h exposure to 1 mM ACPC (which was removed 30 min before addition of 25 mu M NMDA) also caused cells to b e significantly less responsive to the neurotoxic effects of NMDA. Pre -exposure to ACPC for shorter intervals (< 1 h) failed to alter subseq uent 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 phe nomena, and (2) sustained exposure to ACPC desensitizes the NMDA recep tor complex.