Mohamed M. A. Elmazar

Maternal factors influencing development of embryos from mice superovulated with gonadotropins

In NMRI mice superovulation with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) increased mating rate, number of implantation sites, rate of advanced and delayed resorptions, as well as retarded sternebral ossification and cleft palate. On day 3 of gestation in preimplantation embryos, cell number and mitotic index were lower after superovulation than after spontaneous ovulation. However, when preimplantation embryos from superovulated and control females were transferred on day 3 of pregnancy to pseudopregnant recipients (10 embryos per female) no differences could be detected between the two groups of fetuses at term. The results of the embryo transfer experiments indicate that abnormal embryonic development after superovulation with gonadotropins is predominantly induced by effects of the hormone treatment on the maternal uterine environment.

On the development of alternative antiepileptic drugs : lack of enantioselectivity of the anticonvulsant activity, in contrast to teratogenicity, of 2-n-propyl-4-pentenoic acid and 2-n-propyl-4-pentynoic acid, analogues of the anticonvulsant drug valproic acid

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Trimethoprim potentiates valproic acid-induced Neural Tube Defects (NTDs) in mice

The antiepileptic drug valproic acid (VPA) may produce NTDs because of interference with folate metabolism. Therefore, the possible interactions of VPA with the dihydrofolate reductase inhibitor trimethoprim (TM) was investigated. The combination of TM with sulfamethoxazol is used for treatment of urinary infections, the most common complications of pregnancy. TM (80 and 160 mg/kg) was given i.p. and orally, 0.5 and 1 h, respectively, prior to valproic acid (VPA, 300 and 400 mg/kg, s.c.) in day 8 pregnant NMRI mice. Fetuses were examined for exencephaly, resorptions, and fetal weight retardation on day 18 of gestation. TM (160 mg/kg, i.p.) produced no exencephaly or embryolethality, but increased fetal weight. Administration of TM (80 mg/kg, i.p.) increased VPA-induced exencephaly and fetal weight retardation but not embryolethality. Exencephaly rates induced by VPA (300 and 400 mg/kg) were 4% and 12.9% and were increased by coadministration of TM to 22.7% and 42.5%, respectively (P < 0.01). Oral TM also increased VPA-induced exencephaly and fetal weight retardation but with lower potency than i.p. injection. The observed effects were not due to altered VPA pharmacokinetics. These results support the view that VPA-induced neural tube defects may be mediated via an interaction with folate metabolism, and advise against TM-use in VPA-treated epileptics during pregnancy.

Amniotic fluid cholinesterase of valproate-induced exencephaly in the mouse: an animal model for prenatal diagnosis of neural tube defects

After a single administration of the antiepileptic drug valproic acid (VPA; i.p.: 600 mg/kg) on day 8 of gestation in the mouse embryotoxicity and amniotic fluid (AF) cholinesterase (ChE) were evaluated on day 16 of gestation. VPA treatment induced an increase in embryolethality, neural tube defects (exencephaly), cleft palate, deformed vertebrae, open eyes, and a reduction in fetal weight. In VPA-exposed fetuses AF total ChE (TChE) activity of exencephalic fetuses was higher than that of normal fetuses. However, in 3 out of 110 normal fetuses of the control group TChE activity was found in the AF. There was no correlation between blood contamination of AF and its TChE activity, either in non-exencephalic control or treated embryos. Using ethopropazine as a “pseudo”-ChE inhibitor in vitro, the percentage of acetyl-ChE in blood-contaminated AF was similar to that of fetal rather than maternal serum, indicating that AF was contaminated with fetal and not with maternal blood. VPA-induced exencephaly in mice may provide an animal model to further investigate biochemical markers for prenatal diagnosis of neural tube defects.