Prophylactic Effects of Melatonin on Sodium Valproate-Induced Neural Tube Defects and Skeletal Malformations in Rat Embryos

Abstract

Problem statement: Some reports showed the teratogenic effects of sodium valproate can be prevented by application of antioxidant drugs and stimulation of the maternal immune system. Therefore, in this study, the prophylactic effect of melatonin on teratogenic effects of sodium valproate was compared. Approach: This study was performed on 31 pregnant rats that were divided into five groups. Control group received normal saline and test groups received sodium valproate (300 mg kg ), intraperitonealy at 8-9th days of gestation, respectively. Fetuses were collected at 20th day of gestation and after determination of weight and length; they were stained by Alizarin red-Alcian blue method. Results: Cleft palate, spina bifida and exencephaly incidence were 17.70, 20 and 20% in fetuses of rats that received only sodium valproate. Cleft palate, spina bifida and exencephaly incidence were 4.16, 8.33 and 8.33% range in group which received sodium valproate plus melatonin (5 mg kg −1 ), respectively. However, Cleft palate, spina bifida and excencaphaly incidence were 4/76, 0 and 0% in group which received sodium valproate plus melatonin (10 mg kg −1 ), respectively. The mean of weight and length of animals' fetuses that received melatonin were significantly greater than those received only sodium valproate. Conclusion: It is concluded that melatonin with dose of 10 mg kg −1 had significantly more prophylactic effect than melatonin with dose of 5 mg kg −1 on incidence of sodium valproate-induced skeletal malformations.

A rat model of valproate teratogenicity from chronic oral treatment during pregnancy

“…For example, Sprague Dawley rats administered VPA at 400 mg/kg/d via oral gavage from gestational day 7-18 exhibited cardiovascular, vertebral, and rib defects, as well as hypoplastic bladder, ectrodactyly, and hydronephrosis, whereas higher doses resulted in embryo resorption and lower doses resulted in less severe malformations. 11 Approximately 20% of the offspring of Wistar rats administered VPA at 300 mg/ kg intraperitoneally (ip) on the 8-9th day of pregnancy were found to have birth defects, such as spina bifida, cleft palate, and exencephaly, 12 whereas receiving 600 mg/kg VPA subcutaneously (sc) twice on gestational day 9 resulted in spina bifida occulta in 100% of exposed fetuses. 13 Mouse studies have found strain-dependent effects, with some strains exhibiting higher rates of rib fusion following 200 mg/kg ip VPA than others, 14 suggesting an underlying genetic susceptibility.…”