N‐methyl‐D‐aspartate receptor agonists modulate homocysteine‐induced developmental abnormalities

Abstract

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.

Folic acid and homocysteine affect neural crest and neuroepithelial cell outgrowth and differentiation in vitro

“…This could be due to the ability of homocysteine to inhibit the NMDA receptor, which is involved in intracellular and intercellular processes that are central to neural tube closure and neural crest migration (Rosenquist et al, 1999;Rosenquist and Finnell, 2001).…”

Homocysteine inhibits cardiac neural crest cell formation and morphogenesis in vivo

“…The concentration and timing of homocysteine treatment was identical to that used in teratogenic studies performed by Rosenquist et al (1996Rosenquist et al ( , 1999 and to that used in our previous studies on the effect of homocysteine on neural crest cell migration in vitro (Brauer and Rosenquist, 2002). Under these conditions, the types and incidence of homocysteine-induced defects (54% incidence of visible defects in homocysteine-treated embryos vs. a 9% incidence in Ringer's-treated embryos by Hamburger-Hamilton stage 10 -11) paralleled those reported in these studies.…”

“…Elevated homocysteine leads to congenital defects resembling neural crest cell ablation and, as such, likely target several key fundamental processes necessary for proper neural crest development, which may include altering neural crest cell specification and formation, neural crest cell migration and differentiation, and neural crest cell proliferation (Rosenquist et al, 1996(Rosenquist et al, , 1999. Previous studies demonstrate elevated homocysteine alters neural crest cell migratory behavior, cell shape, and neural crest differentiation in vitro (Brauer and Rosenquist, 2002;Boot et al, 2003), but little else is known regarding the effect homocysteine has on neural crest development in vivo.…”

High‐affinity folate receptor in cardiac neural crest migration: A gene knockdown model using siRNA

“…Groups were compared using a Student's t-test modified for small groups with differing n (Rosenquist et al, 1999):…”

“…Embryonic phenotypes and the rate of occurrence of major structural defects were analyzed from gross specimens and from reconstructed histological sections, according to our published method (Rosenquist et al, 1990(Rosenquist et al, , 1996(Rosenquist et al, , 1999Latacha and Rosenquist, 2005).…”