Excitotoxicity in the embryonic chick spinal cord.
Recent evidence implicates excitatory amino acids (EAAs), acting as excitotoxic agents, in the pathogenesis of neurological disorders involving the spinal cord. In this study, we used the chick embryo spinal cord as an in vitro model for studying the sensitivity of spinal neurons to the excitotoxic effects of EAA agonists. Compounds tested include the prototypic receptor-specific agonists, N-methyl-D-aspartate (NMDA), quisqualic acid (Quis), and kainic acid (KA), and the plant-derived excitotoxic food poisons, beta-N-oxalylamino-L-alanine, beta-N-methylamino-L-alanine, and domoic acid. Each agonist induced concentration-dependent acute degeneration of neurons distributed throughout the spinal cord. These cytopathological changes consisted of acute edematous degeneration of dendrosomal structures in the dorsal horn and intermediate zone, and dark cell changes with intracytoplasmic vacuolization of motor neurons; this damage is identical to that induced by excitotoxin agonists in other regions of the central nervous system. The NMDA receptor-specific antagonist MK-801 completely blocked toxicity of NMDA, and the nonNMDA antagonist CNQX preferentially blocked the toxicity of Quis- and KA-type agonists in the spinal cord. Our findings suggest that (1) the majority of spinal neurons have all three subtypes of EAA receptors, making them acutely vulnerable to excitotoxin exposure; and (2) EAA antagonists are effective in preventing excitotoxin-induced damage of the spinal cord.
Stewart
G R
GR
Laboratory of Neurophysiology, National Institute of Mental Health, NIH Animal Center, Poolesville, MD 20837.
Olney
J W
JW
Pathikonda
M
M
Snider
W D
WD
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000599:Amino Acids, Diamino / Q000494:pharmacology; D000818:Animals; D002642:Chick Embryo; D000087522:Cyanobacteria Toxins; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D016202:N-Methylaspartate / Q000494:pharmacology; D009410:Nerve Degeneration / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D005971:Glutamates; D009498:Neurotoxins; D011810:Quinoxalines; C001824:beta-N-methylamino-L-alanine; D015091:beta-Alanine; C100126:oxalyldiaminopropionic acid; D007051:Ibotenic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D016318:Quisqualic Acid; C012301:domoic acid; D007608:Kainic Acid