Eur J Anat, 4 (1): 23-33 (2000)

Valproate induced effects on development in the rat are partially prevented by folinic acid and S-adenosylmethionine

Ubeda N., Alonso-Aperte E., Perez-Miguelsanz J., Varela-Moreiras G.

Seccion Nutricion y Bromatologia, Facultad de Ciencias Exp. y Tecnicas, Universidad San Pablo CEU, ctra. Boadilla del Monte km 5,3, 28668 Madrid, Spain

ABSTRACT Valproic acid (VPA) is a teratogenic agent that induces a wide range of tissue alterations, including neural tube defects (NTD) and skull malformations. There is an established dose-dependent effect of VPA and types of malformations in rat. The aim of the present study was to determine morphological, histological and immunohistochemical alterations under an assumedly non teratogenic VPA exposure. Potential prevention by coadministration with folinic acid (FA) and S-adenosylmethionine (SAM) was also assessed. Wistar rats were treated during gestation with VPA (300 mg/kg/d on days 8, 9, and 10), either alone or in combination with FA (4 mg/kg/d on days 8, 9, and 10) or SAM (10 mg/kg/d from days 1 to 10). Rats were terminated on day 21, and implantation sites were counted. VPA induced a lower fertility rate due to a higher number of resorptions, which were reduced by coadministration of either FA or SAM. Foetal weight and length were unaffected by VPA treatment. Hepatic injury was observed in foetuses treated with VPA. Studies with specific antibodies against Kupffer cells and T-lymphocytes also showed that Kupffer cells appeared more frequently in the VPA+FA and VPA+SAM groups, whereas folinic acid and exogenous SAM were able to reverse the decrease in VPA-induced foetal liver T-lymphocyte cells. VPA treatment resulted in skeletal modifications in the skull, appendicular bones, vertebrae and ribs. Folate was able to prevent these defects, whereas SAM-coadministration did not show this protective action. The results are discussed on the basis that VPA may induce other potential alterations different from NTD whose long-term effects are not well understood at present.

Keywords: folinic acid, s adenosylmethionine, valproic acid, animal experiment, animal model, animal tissue, article, congenital malformation, controlled study, dose response, drug effect, female, female fertility, fetus malformation, immunohistochemistry, Kupffer cell, liver injury, neural tube defect, nonhuman, pregnancy, rat, rat strain, T lymphocyte, teratogenesis