Protective effect of riluzole on excitatory amino acid-mediated neurotoxicity in motoneuron-enriched cultures.
Excitatory amino acid-mediated neurotoxicity was investigated in motoneuron-enriched cultures from fetal rats at 12-14 days of gestation. The cultures were mainly composed of differentiated motoneurons identified by choline acetyl transferase and calcitonin gene-related peptide (CGRP) immunoreactivity. Addition of glutamate (600 microM) to the conditioned medium induced no acute neuronal swelling. However, it was followed by a widespread neuronal degeneration over the next 24 h, accounting for 77% of the total cell number. Glutamate toxicity was dose dependent, with an EC50 around 300 microM. Treatment for 24 h with the agonists, N-methyl-D-aspartate (NMDA, 100 microM), kainate (500 microM) or RS-alpha-amino-3-hydroxy-5-methyl-4-isoxalopropionate (AMPA, 10 microM), also induced a significant cell loss. Riluzole (2 amino 6-trifluoromethoxybenzothiazole), a compound known to interfere with glutamatergic transmission pre- and postsynaptically, significantly reduced glutamate and NMDA neurotoxicity in a dose-dependent manner. These results suggest that a prolonged activation of one or more subtypes of ionotropic excitatory amino acid receptors can lead to motoneuron degeneration in vitro, and provide direct experimental evidence supporting the neuroprotective effect of riluzole in cultured motoneurons.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002493:Central Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D018846:Excitatory Amino Acids / Q000633:toxicity*; D018698:Glutamic Acid / Q000633:toxicity; D007608:Kainic Acid / Q000633:toxicity; D009046:Motor Neurons / Q000187:drug effects*; D016202:N-Methylaspartate / Q000633:toxicity; D051381:Rats; D017459:Receptors, Amino Acid / Q000819:agonists; D019782:Riluzole; D013844:Thiazoles / Q000627:therapeutic use*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D017459:Receptors, Amino Acid; D013844:Thiazoles; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D019782:Riluzole; D007608:Kainic Acid