A novel NMDA receptor antagonist protects against N-methyl-D-aspartate- and glutamate-induced neurotoxicity in the goldfish retina.
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 EC50 value of 3.6 microM, whereas the depolarization of these neurons evoked by alpha-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.
Tyan
S H
SH
Department of Chemistry, National Chung-Cheng University, Chia-Yi, Taiwan, ROC.
Sue
T Y
TY
Hon
Y S
YS
Gean
P W
PW
Chang
Y C
YC
D000818:Animals; D004347:Drug Interactions; D018698:Glutamic Acid / Q000633:toxicity*; D006054:Goldfish / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012160:Retina / Q000187:drug effects*; D012164:Retinal Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid