A novel NMDA receptor antagonist protects against N-methyl- d-aspartate- and glutamate-induced neurotoxicity in the goldfish retina

Abstract

4( R)-(3-Phenylpropyl)-2( S)-glutamic acid, C (3), is a synthetic analogue of l-glutamate. This analogue reversibly inhibits the membrane depolarization of neurons in the CA1 region of rat hippocampal slices evoked by N-methyl- d-aspartate (NMDA), with an EC 50 value of 3.6 μM, whereas the depolarization of these neurons evoked by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid is not inhibited by C (3). Analyses of the inhibitory effect of C (3) on NMDA-evoked currents of dissociated rat hippocampal neurons further revealed that C (3) acts as a competitive antagonist of NMDA receptors and that the inhibitory action of C (3) is not use-dependent. Using goldfish retina as a model, we found that the neuronal damage produced by glutamate or by NMDA was effectively prevented by C (3). Incubation of retinas with high concentrations of C (3), up to 1 mM, did not induce pathomorphological changes in retinal neurons. These results suggest that C (3) is a useful neuroprotectant against excitotoxic damage of neurons.