N-methyl-D-aspartate receptor agonists modulate homocysteine-induced developmental abnormalities.
We showed previously that the induction of neural crest (NC) and neural tube (NT) defects is a general property of N-methyl-D-aspartate receptor (NMDAR) antagonists. Since homocysteine induces NC and NT defects and can also act as an NMDAR antagonist, we hypothesized that the mechanism of homocysteine-induced developmental defects is mediated by competitive inhibition of the NMDAR by homocysteine. If this hypothesis is correct, homocysteine-induced defects will be reduced by NMDAR agonists. To test the hypothesis, we treated chicken embryos during the process of neural tube closure with sufficient homocysteine thiolactone to induce NC and NT defects in approximately 40% of survivors or with homocysteine thiolactone in combination with each of a selected set of NMDAR agonists in 0. 05-5000 nmol doses. Glutamate site agonists selected were L-glutamate and N-methyl-D-aspartate. Glycine site agonists were glycine, D-cycloserine, and aminocyclopropane-carboxylic acid. Glycine was the most effective overall, reducing defects significantly at two different doses (each P>0.001). These results support the hypothesis that homocysteine may affect NC and NT development by its ability to inhibit the NMDAR. One potentially important consequence of this putative mechanism is that homocysteine may interact synergistically with other NMDAR antagonists to enhance its effect on development.
Rosenquist
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University of Nebraska Medical Center, Omaha, Nebraska 68198-6395, USA. throsenq@unmc.edu
Schneider
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Monogham
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D000818:Animals; D002642:Chick Embryo; D003523:Cycloserine / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D006710:Homocysteine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D016202:N-Methylaspartate / Q000494:pharmacology; D009420:Nervous System / Q000187:drug effects / Q000196:embryology*; D009421:Nervous System Malformations / Q000139:chemically induced* / Q000517:prevention & control; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D013723:Teratogens / Q000633:toxicity*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D013723:Teratogens; D006710:Homocysteine; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003523:Cycloserine; D005998:Glycine