"ALTERED PLASMA ZINC LEVEL CONTRIBUTES TO THE DEVELOPMENTAL TOXICITY OF VALPROIC ACID IN SKELETAL SYSTEM OF RAT"

Abstract

Valproic acid is one of the main antiepileptic drugs. There is an increased risk of neural tube defects and axial skeletal malformations among infants born to women who had received valproic acid. There is a hypothesis that one biochemical abnormality underlying the teratogenicity of valproic acid is a drug-induced reduction in maternal plasma zinc .In the present experimental study mated rats were divided into four groups of 8 animals each [control, valproic acid (VPA), valproic acid + zinc (VPA+ Zn) and zinc (Zn) groups]. The VPA group received 300 mg/kg valproic acid, daily.The control group received an equal volume of 0.9% NaCl. The VPA+ Zn group received 300 mg/kg VPA and 30 mg/kg zinc sulfate and the Zn group received 30 mg/kg zinc sulfate, daily. Valproic acid, NaCl, and Zn were administered intraperitonealy from day 6 through day 15 of gestation. On day 16, six rats of each group were authanized and the other rats were scarified on gestational day (GD) 20 to evaluate the skeletal system among the elder fetuses. Blood was drawn to determine plasma zinc. The data were analyzed by using analysis of variance (Kruskal -Wallis test). The zinc concentration in the plasma of rats treated with valproic acid was significantly lower than those of the other groups on 16 GD (P=0.004). Some anomalies such as hydrocephaly, spina bifida, hemivertebrate, and rib malformations were seen in VPA treated group. Low percentage of rib anomalies and spina bifida were observed in the VPA+ Zn treated group while no skeletal anomalies were seen in Zn and control groups. The results from the present experiment support the hypothesis that one of the biochemical abnormalities causing the teratogenicity of VPA is a drug–induced maternal plasma zinc deficiency, and possibly, it may also result in reduction of embryonic Zn.