NEUROPROTECTIVE ACTIONS OF 1-AMINOCYCLOPROPANECARBOXYLIC ACID (ACPC) - A PARTIAL AGONIST AT STRYCHNINE-INSENSITIVE GLYCINE SITES

1-Aminocyclopropanecarboxylic acid is a high affinity ligand with part ial agonist properties at strychnine-insensitive glycine sites associa ted with the N-methyl-D-aspartate subtype of glutamate receptors. Sinc e occupation of these sites appears required for operation of N-methyl -D-aspartate receptor coupled cation channels, it was hypothesized tha t a glycine partial agonist could function as an N-methyl-D-aspartate antagonist. This hypothesis was examined by evaluating the in vivo and in vitro neuroprotective actions of 1-aminocyclopropanecarboxylic aci d. 1-Aminocyclopropanecarboxlic acid (150-600 mg kg(-1)) administered to gerbils five minutes following twenty minutes of forebrain ischemia significantly improved seven day survival; the optimal dose (300 mg k g(-1)) increased 7 day survival >4-fold, from 20% to 92%. Survival of hippocampal CA1 neurons (guantitated 7 days post-ischemia) was signifi cantly (similar to 3-fold) increased by the 600 mg kg(-1) dose. Seven day survival was not significantly increased when the interval between reperfusion and drug administration (300 mg kg(-1)) was increased fro m 5 to 30 min. In cerebellar granule cell cultures, NMDA combined with a saturating concentration of glycine (10 mu M) resulted in a 500% in crease in cGMP levels. cGMP levels were increased by 100% over basal w hen NMDA was combined with a saturating (10 mu M) concentration of ACP C, indicating that in this measure, the efficacy of ACPC relative to g lycine was similar to 0.2. Consistent with previous findings, 1-aminoc yclopropanecarboxylic acid significantly reduced glutamate-induced neu rotoxicity in cerebellar granule cell cultures. ACPC was most effectiv e in blocking neurotoxicity at glutamate concentrations producing low to moderate levels of cell death. As glutamate concentrations increase d and cell death approached a maximum, the neuroprotective action of A CPC was abolished. The latter findings are consistent with the action of a partial agonist in a system requiring occupation of two distinct but interacting sites. Based on the neuroprotective actions of 1-amino cyclopropanecarboxylic acid in these and other models, a Phase I clini cal trial of ACPC has been initiated.