Effects of excitatory amino acids on neuromuscular development in the chick embryo.
To investigate the presumptive role of excitatory amino acids (EAAs) in the regulation of normally occurring motoneuron (MN) death, chick embryos were treated with the glutamate receptor antagonists dizocilpine maleate and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium. Both failed to alter the number of surviving MNs at the end of the critical period of programmed cell death. However, treatment with 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, a competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, was able to rescue a significant number of MNs from death. Treatment with several EAA agonists induced extensive excitotoxic lesions in the spinal cord. MN degeneration induced by excitotoxins exhibited changes characteristic of necrosis rather than apoptosis. However, when either 0.5 or 1 mg of NMDA was applied acutely on embryonic day (E) 7, about 50% of treated embryos failed to exhibit NMDA-induced excitoxicity but rather showed a clear reduction in the number of pyknotic MNs. This apparent neuroprotective effect of NMDA was also observed in a subset of embryos chronically treated with NMDA, in which an excessive number of MNs was detected when examined on E9. Surprisingly, in the same experiment other embryos showed either normal or highly reduced MN numbers. Embryos with motoneuronal depletion induced by NMDA also showed a delayed impairment of later neuromuscular development with the appearance of degenerative changes in surviving MNs and apoptosis of skeletal muscle cells. Because some of the alterations reported here are similar to those described in MN diseases, our experimental model may be useful for gaining insights into the mechanisms that control both developmentally regulated and pathological MN death.
Calderó
J
J
Departament de Cièncias Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, Catalonia, Spain.
Ciutat
D
D
Lladó
J
J
Castán
E
E
Oppenheim
R W
RW
Esquerda
J E
JE
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002642:Chick Embryo / Q000187:drug effects* / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000494:pharmacology*; D005121:Extremities; D018698:Glutamic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000196:embryology; D009435:Synaptic Transmission / Q000187:drug effects*
D018690:Excitatory Amino Acid Agonists; D018846:Excitatory Amino Acids; D018698:Glutamic Acid; D016202:N-Methylaspartate