Calderó J, Ciutat D, Lladó J, Castán E, Oppenheim R W, Esquerda J E
Departament de Cièncias Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, Catalonia, Spain.
J Comp Neurol. 1997 Oct 13;387(1):73-95.
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.
为了研究兴奋性氨基酸（EAA）在调节正常发生的运动神经元（MN）死亡中的假定作用，用谷氨酸受体拮抗剂马来酸氯氮平和1,2,3,4 - 四氢 - 6 - 硝基 - 2,3 - 二氧代 - 苯并[f]喹喔啉 - 7 - 磺酰胺二钠处理鸡胚。两者均未能改变程序性细胞死亡关键期结束时存活MN的数量。然而，用竞争性N - 甲基 - D - 天冬氨酸（NMDA）受体拮抗剂3 - （2 - 羧基哌嗪 - 4 - 基） - 丙基 - 1 - 膦酸处理能够挽救大量MN免于死亡。用几种EAA激动剂处理可在脊髓中诱导广泛的兴奋性毒性损伤。由兴奋性毒素诱导的MN变性表现出坏死而非凋亡的特征性变化。然而，当在胚胎第（E）7天急性应用0.5或1mg NMDA时，约50%的处理胚胎未表现出NMDA诱导的兴奋性毒性，而是显示固缩MN的数量明显减少。在慢性用NMDA处理的一部分胚胎中也观察到了NMDA这种明显的神经保护作用，在E9检查时发现其中有过多数量的MN。令人惊讶的是，在同一实验中，其他胚胎显示MN数量正常或大幅减少。由NMDA诱导运动神经元耗竭的胚胎还表现出后期神经肌肉发育的延迟损伤，存活MN出现退行性变化，骨骼肌细胞发生凋亡。因为这里报道的一些改变与MN疾病中描述的相似，我们的实验模型可能有助于深入了解控制发育调节性和病理性MN死亡的机制。
