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Effects of excitatory amino acids on neuromuscular development in the chick embryo
1Departament de Cièncias Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, Catalonia, Spain.
Abstract:
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.
Insights
Excitatory amino acids (EAAs) play a complex role in motoneuron (MN) death. While some antagonists had no effect, an N-methyl-D-aspartic acid (NMDA) receptor antagonist rescued MNs, suggesting NMDA
Area of Science:
- Neuroscience
- Developmental Biology
- Neuroprotection
Background:
- Excitatory amino acids (EAAs) are neurotransmitters implicated in neuronal development and death.
- Motoneuron (MN) death is a critical process during embryonic development, with potential links to neurological diseases.
- The precise role of specific glutamate receptors in regulating programmed MN death remains incompletely understood.
Purpose of the Study:
- To investigate the role of excitatory amino acids (EAAs) in the regulation of naturally occurring motoneuron (MN) death during embryonic development.
- To explore the potential neuroprotective or excitotoxic effects of N-methyl-D-aspartic acid (NMDA) receptor modulation on MN survival.
- To establish an experimental model for studying both developmental and pathological MN death.
Main Methods:
- Chick embryos were treated with various glutamate receptor antagonists, including dizocilpine maleate and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium.
- The competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid was administered.
- Excitatory amino acid (EAA) agonists and NMDA were applied acutely and chronically to assess effects on MN survival and spinal cord pathology.
Main Results:
- Glutamate receptor antagonists dizocilpine maleate and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium did not alter surviving MN numbers.
- The NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid significantly rescued motoneurons (MNs) from programmed cell death.
- NMDA treatment produced varied effects, including excitotoxicity, neuroprotection (reduced pyknotic MNs), and developmental impairments, suggesting a complex role.
Conclusions:
- Specific NMDA receptor antagonism can protect motoneurons (MNs) from developmental cell death.
- NMDA receptor activation exhibits complex, dose- and time-dependent effects on MN survival, ranging from excitotoxicity to apparent neuroprotection.
- This experimental model offers insights into mechanisms underlying both normal developmental and pathological motoneuron death, relevant to MN diseases.