Excitatory amino acid neurotoxicity in cultured retinal neurons: involvement of N-methyl-D-aspartate (NMDA) and non-NMDA receptors and effect of ganglioside GM1.
Cultures of chicken day 8 embryo retinal cells, essentially free of contaminating non-neuronal elements, were used to examine the neurotoxicity of various excitatory amino acid transmitter receptor agonists. At 7 days in vitro, N-methyl-D-aspartate (NMDA), following 24 hr exposure to 0.1-1.0 mM, destroyed 60-70% of the multipolar neurons, but apparently spared photoreceptors. The cytotoxic effect of NMDA was prevented by extracellular Mg2+ or phencyclidine, suggesting a role for the NMDA ion channel; competitive NMDA antagonists were also neuroprotective. The mixed excitatory amino acid receptor agonist glutamate (0.1-1.0 mM) was also neurotoxic (approximately 70% loss of multipolar neurons) and strongly blocked by NMDA (but weakly by non-NMDA) antagonists and Mg2+, indicating a major action at NMDA receptors. As with NMDA, glutamate did not appear to affect photoreceptors. The neurotoxic action of kainate against multipolar retinal neurons, as reported by others, was confirmed here. Kainate neuronal injury was sensitive to the quinoxalinedione non-NMDA antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyanoquinoxaline-2,3-dione (CNQX), but not to Mg2+ or phencyclidine. Ibotenate and quisqualate, even at millimolar concentrations, were not neurotoxic. The monosialoganglioside GM1 was also effective in reducing NMDA and non-NMDA agonist neurotoxicity to retinal neurons. Maximal ganglioside benefit required 1-2 hr of pretreatment with 100-200 microM GM1. The percentage of multipolar neurons remaining after the neurotoxin insult approximately doubled with GM1 treatment. Gangliosides may thus have a therapeutic potential in excitatory amino acid-initiated neuropathologies.
Facci
L
L
Fidia Research Laboratories, Abano Terme, Italy.
Leon
A
A
Skaper
S D
SD
D000596:Amino Acids / Q000633:toxicity*; D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D005677:G(M1) Ganglioside / Q000494:pharmacology*; D005971:Glutamates / Q000633:toxicity; D007608:Kainic Acid / Q000633:toxicity; D009422:Nervous System Diseases / Q000139:chemically induced*; D009474:Neurons / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012160:Retina / Q000187:drug effects*
D000596:Amino Acids; D005971:Glutamates; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D005677:G(M1) Ganglioside; D007608:Kainic Acid