The Effects of Valproic Acid on Sciatic Nerve of Fetal Rats and Protective Effects of Folic Acid and Vitamin E

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Abstract

We aimed to investigate the potential harmful effects of maternal valproic acid (VPA) on fetal sciatic nerve, and the protective effects of vitamin E (Vit E) and folic acid (FA) on fetal rats. Valproic acid (400mg/kg), folic acid (400mg/kg) and vitamin E (250 mg/kg) were administered to rats on each of gestation days 8-10. All fetuses were collected on gestation day 20. With thin sections of biopsies, sciatic nerve of fetuses were stained with uranyl acetat and were examined under transmission electron microscope. The fetuses (n:36) were divided into five groups: control, vpa, vpa+fa, vpa+vit e and vpa+fa+vit e groups. In each group; drug procedure, surgical procedure and histological methods were performed. Later, weights and lengths of fetuses in each group were compared and analyzed by One-Way Anova test. Administration of single doses of valproic acid (400 mg/kg) resulted in weight and length loss between control and vpa group. However, length and weight differences between the other groups were not significant. The histopathological findings of control group was normal. In vpa group, it showed extensive degenerative changes especially in myelin coat. In addition, most prominent finding in this group was condensation of collagen fibers in extensively demyelinated samples, while moderately effected areas were relatively normal. Both vpa+fa and vpa+ vit e groups exhibited similar ultrastructural changes, reflecting minimal to moderate degenerative changes. In vpa+fa+vit e group had almost the normal structure. Administration of single doses of valproic acid (400 mg/kg) resulted in a deteriorative effect on sciatic nerve at ultrastructural level. Administration of FA and Vit E had a protective effect to prevent the degenerative changes to a certain degree. Combination of FA and Vit E together following VPA administration had a more potent protective effect. The objective of the present study is to analyze histopathologic changes which may occur in a high risk experimental model after the administration of valproic acid. In addition, protective roles of the administration of folic acid and vitamin E are assessed.

Translated abstract

El objetivo fue investigar los posibles efectos perjudiciales del ácido valproico (AVP) materno sobre el nervio ciático en fetos y los efectos protectores de la vitamina E (Vit E) y ácido fólico (AF) en fetos de ratas. Se administraron a ratas ácido valproico (400mg/kg), ácido fólico (400mg/kg) y vitamina E (250 mg/kg) en cada uno de los días de gestación 8-10. Todos los fetos fueron recogidos a los 20 días de gestación. Finas secciones de biopsias obtenidas de los nervios ciáticos de fetos fueron teñidos con acetato de uranilo y examinados bajo microscopio electrónico de transmisión. Los fetos (n: 36) fueron divididos en cinco grupos: control, avp, avp+af, avp+vit e y avp+fa+vit e. En cada grupo, se realizaron los procedimiento farmacológicos, quirúrgicos y los métodos histológicos. Los pesos y longitudes de los fetos de cada grupo fueron comparados y analizados usando la prueba One-Way Anova. La administración de dosis únicas de ácido valproico (400 mg / kg) resultó en la pérdida del peso la longitud entre el control y el grupo apv. Sin embargo, las diferencias en la longitud y el peso entre los otros grupos no fueron significativas. Los hallazgos histopatológicos del grupo control fueron normales. En el grupo avp, se mostró especialmente cambios degenerativos en la mielina que envuelve al nervio periféricamente. Además, predominatemente se encontró en las muestras de este grupo fibras colágenas condensadas y zonas ampliamente desmielinizadas, mientras que las zonas moderadamente afectadas eran relativamente normales. Ambos grupos avp+fa y avp+vit e exhibieron cambios ultraestructurales similares, lo que supone un mínimo o moderado cambio degenerativo. El grupo avp+fa+vit e tuvo casi una estructura normal. La administración de dosis únicas de ácido valproico (400 mg / kg) produjo un efecto sobre el deterioro del nervio ciático a nivel ultraestructural. La administración de la AF y vitamina E tienen un efecto protector, en cierta medida, para evitar la cambios degenerativos. La combinación de AF y vitamina E, junto a la ulterior administración de AVP tienen un efecto protector más potente. El objetivo del presente estudio fue analizar los cambios histopatológicos que pueden ocurrir en un modelo experimental de alto riesgo después de la administración de ácido valproico. Además, fueron evaluadas las funciones de protección de la administración de ácido fólico y la vitamina E.

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Folic acid antagonists during pregnancy and the risk of birth defects.

Douglas A. Mitchell, A. Walker, Martha M. Werler … (2000)

Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinary tract defects in their infants. We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations. We compared data on exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors and to certain antiepileptic drugs for 3870 infants with cardiovascular defects, 1962 infants with oral clefts, and 1100 infants with urinary tract defects with data for 8387 control infants with malformations the risk of which is not reduced after vitamin supplementation. Mothers were interviewed within six months after delivery about their medication use. The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors during the second or third month after the last menstrual period, as compared with infants whose mothers had no such exposure, were 3.4 (95 percent confidence interval, 1.8 to 6.4) and 2.6 (95 percent confidence interval, 1.1 to 6.1), respectively. The relative risks of cardiovascular defects, oral clefts, and urinary tract defects after maternal exposure to antiepileptic drugs were 2.2 (95 percent confidence interval, 1.4 to 3.5), 2.5 (95 percent confidence interval, 1.5 to 4.2), and 2.5 (95 percent confidence interval, 1.2 to 5.0), respectively. Use of multivitamin supplements containing folic acid diminished the adverse effects of dihydrofolate reductase inhibitors, but not that of antiepileptic drugs. Folic acid antagonists, which include such common drugs as trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbital, and primidone, may increase the risk not only of neural-tube defects, but also of cardiovascular defects, oral clefts, and urinary tract defects. The folic acid component of multivitamins may reduce the risks of these defects.

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Methionine reduces the valproic acid-induced spina bifida rate in mice without altering valproic acid kinetics.

K. Ehlers, M M Elmazar, H Nau (1996)

The antiepileptic drug valproic acid (VPA) is an established human teratogen causing spin bifida aperta. We recently developed a mouse model in which spina bifida aperta and occulta are induced with VPA. In a search for protection against neural tube defects, we investigated the effect of methionine on the incidence of VPA-induced spina bifida in the mouse. To induce spina bifida, we injected VPA (350 mg VPA-Na/kg body weight) subcutaneously three times on d 9 of gestation at 0, 6 and 12 h. In some mice, L-methionine (3 x 70 mg/kg body weight) was injected intraperitoneally 30 min before each VPA administration. When fetuses were examined on d 18, methionine treatment slightly reduced the VPA-induced spina bifida aperta rate from 5 to 1% (P > 0.05, no significant difference). The incidence of VPA-induced spina bifida occulta (90%) was significantly lower (28%) when methionine was also administered (P < 0.05). Examination on d 10 showed that the number of embryos in the mice administered VPA and methionine having an open neuroporus posterior was significantly lower than in mice administered VPA alone (P < 0.05). Pharmacokinetic studies indicated that VPA concentrations in maternal plasma and embryo did not differ between the two groups. Methionine reduces VPA-induced spina bifida in mice without altering VPA kinetics.