A NOVEL NMDA RECEPTOR ANTAGONIST PROTECTS AGAINST N-METHYL-D-ASPARTATE-INDUCED AND GLUTAMATE-INDUCED NEUROTOXICITY IN THE GOLDFISH RETINA

4(R)-(3-Phenylpropyl)-2(S)-glutamic acid, C-(3), is a synthetic analog ue of L-glutamate. This analogue reversibly inhibits the membrane depo larization of neurons in the CA1 region of rat hippocampal slices evok ed by N-methyl-D-aspartate (NMDA), with an EC(50) value of 3.6 mu M, w hereas the depolarization of these neurons evoked by lpha-amino-3-hydr oxy-5-methyl-4-isoxazolepropionic acid is not inhibited by C-(3). Anal yses of the inhibitory effect of C-(3) On NMDA-evoked currents of diss ociated rat hippocampal neurons further revealed that C-(3) acts as a competitive antagonist of NMDA receptors and that the inhibitory actio n 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 ef fectively prevented by C-(3). Incubation of retinas with high concentr ations of C-(3), UP to 1 mM, did not induce pathomorphological changes in retinal neurons. These results suggest that C-(3) is a useful neur oprotectant against excitotoxic damage of neurons.