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N‐methyl‐D‐aspartate receptor agonists modulate homocysteine‐induced developmental abnormalities
Author(s) -
Rosenquist T. H.,
Schneider A. M.,
Monaghan D. T.
Publication year - 1999
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.13.12.1523
Subject(s) - nmda receptor , homocysteine , glycine , glutamate receptor , antagonist , neural tube , chemistry , receptor , biochemistry , biology , pharmacology , medicine , endocrinology , amino acid , microbiology and biotechnology , embryo
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 ∼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, T. H., Schneider, A. M., and Monaghan, D. T. N‐methyl‐D‐aspartate receptor agonists modulate homocysteine‐induced developmental abnormalities. FASEB J . 13, 1523–1531 (1999)