Opposing effects of excitatory amino acids on chick embryo spinal cord motoneurons: excitotoxic degeneration or prevention of programmed cell death.
Acute administration of a single dose of NMDA on embryonic day (E) 7 or later induces a marked excitotoxic injury in the chick spinal cord, including massive necrotic motoneuron (MN) death. When the same treatment was performed before E7, little, if any, excitotoxic response was observed. Chronic treatment with NMDA starting on E5 prevents the excitotoxic response produced by a later "acute" administration of NMDA. Additionally, chronic NMDA treatment also prevents the later excitotoxic injury induced by non-NMDA glutamate receptor agonists, such as kainate or AMPA. Chronic NMDA treatment also reduces normal MN death when treatment is maintained during the period of naturally occurring programmed cell death (PCD) of MNs and rescues MNs from PCD induced by early peripheral target deprivation. The trophic action of chronic NMDA treatment appears to involve a downregulation of glutamate receptors as shown by both a reduction in the obligatory NR1 subunit protein of the NMDA receptor and a decrease in the kainate-induced Co(2+) uptake in MNs. Both tolerance to excitotoxicity and trophic effects of chronic NMDA treatment are prevented by the NMDA receptor antagonist MK-801. Additionally, administration of MK-801 alone results in an increase in MN PCD. These data indicate for the first time that early activation of NMDA receptors in developing avian MNs in vivo has a trophic, survival-promoting effect, inhibiting PCD by a target-independent mechanism that involves NMDA receptor downregulation.
Lladó
J
J
Unitat de Neurobiologia Cellular, Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, E25198 Lleida, Catalonia, Spain.
Calderó
J
J
Ribera
J
J
Tarabal
O
O
Oppenheim
R W
RW
Esquerda
J E
JE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002642:Chick Embryo; D015536:Down-Regulation; D004361:Drug Tolerance; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009336:Necrosis; D009410:Nerve Degeneration; D009498:Neurotoxins / Q000494:pharmacology*; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D013997:Time Factors
D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate