[Morphological changes induced by valproate and its administration concomitant with folinic acid or S-adenosylmethionine in pregnant rats]. / Alteraciones morfológicas en rata gestante, inducidas por el valproato y su administración conjunta con ácido folínico o S-adenosilmetionina.

Neural tube defects (NTD) are serious congenital abnormalities that have a multifactorial etiology, including both genetic and environmental effectors (for example, diet and/or drugs). Valproic acid (VPA) is a frequently used anti-epileptic drug that has a potentially teratogenic character, as well as the capacity for inducing NTD and other less serious malformations. However, the mechanism of action of VPA has not been clearly established, and it has been suggested that it interferes in the folate cycle and therefore, with the methionine/methylation, possibly through a metabolic blocking of some biomarker that is a key of the cycle, such as for example S-adenosylmethionine (SAM) and folic acid (FA). The objective of the present study is to analyze the morphological and histological changes, which can occur in a high risk experimental model after the administration of VPA as well as for the induction of NTD and other malformations. In addition, the protective roles of the administration of folic acid, 5-formyltetrahydrofolate (FOL) and S-adenosylmethionine (SAM) are assessed. For this pregnant "Wistar" rats classified according to the following treatments: 1) VPA (300 mg/kg/day on days 8, 9, and 10 of the pregnancy); II) VPA (300 mg/kg/day on days 8, 9, and 10 of the pregnancy) and FOL (4 mg/kg/day i.p. on days 8, 9, and 10 of the pregnancy); III) VPA (300 mg/kg/day on days 8, 9, and 10 of the pregnancy) + SAM (10 mg/kg/day, on days 1-10 of the pregnancy); IV) CONTROL (no treatment). VPA decreases the fertility index by 25% compared to the control group, it increases the number of reabsorptions by mother (1.3 +/- 0.5 vs 1.0 +/- 0.5), and decreases the number of fetuses compared to the control (9.0 +/- 1.4 vs. 12.6 +/- 0.9). In the VPA + FOL group, the numbers for these parameters approach those of the control group and the VPA + SAM group is no different from the VPA group, showing no protective factors. With respect to the bone alterations observed, when these are grouped according to whether they affect the skull, trunk, and extremities, it is seen that there are no significant differences between the groups. The histological study and the immunohistochemical analysis show liver alterations in all groups treated, and a lower number of lymphocytes in the VPA group, and a greater number of Kupffer cells, The results are discussed in relation to, first, the effect of VPA per se in the interference of the methionine/methylation cycle, and secondly, with regard to how folic acid and/or S-adenosylmethionine can improve or not some of the harmful effects induced by VPA.

Choline deficiency and methotrexate treatment induces marked but reversible changes in hepatic folate concentrations, serum homocysteine and DNA methylation rates in rats.

OBJECTIVE: The study compared the effects of feeding rats a choline deficient (CD) diet or injecting low doses of methotrexate (MTX) on hepatic folate concentration and distribution, homocysteine (Hcy) concentration and DNA methylation. METHODS: Thirty rats were divided into three groups and were fed either a choline sufficient (CS) or deficient diet (CD), or injected with low doses of MTX (0.1 mg/kg/day) for 2 weeks. Half the animals of each group were sacrificed and the remaining CD and MTX animals were fed repletion diets without methotrexate administration for two additional weeks. RESULTS: CD or MTX resulted in a significantly lower folate concentrations (25-50%) compared to the control group. Folate distribution in the treated animals was associated with elongation of the glutamate chains: higher proportion of hexa (from 14%, control, to 35%, choline, p < 0.05), hepta (from 5% to 16%, p < 0.05), and appearance of octaglutamyl folates. MTX administration resulted in a similar pattern of hepatic folate distribution. Two weeks following the MTX administration and the restoration of an adequate choline diet for 2 weeks restored the hepatic folate levels to the control animals. CONCLUSIONS: Results are discussed based on the possibility that CD and MTX treatment appear to impair the capacity of tissues to incorporate folate in only 2 weeks and affect other biomarkers of one-carbon metabolism such as Hcy concentration and DNA methylation. This adverse picture was partially reversed in a relative short time by simply feeding an adequate CS diet and discontinuing MTX injections.

[Changes in the aortic arch in chick embryos resulting from modified hemodynamic factors]. / Alteración de los arcos aórticos en embriones de pollo como consecuencia de factores hemodinámicos modificados.

Hemodynamic factors acting as modelator agents in the outflow region of great vessels and aortic arches have been studied by many authors. In our study, we have tried to analyse the influence which a modification of some of these factors, as it is an increased blood volume, could cause on truncus and aortic arches, by means of the perfusion of blood from chick embryos of 12-15 days of incubation to receptor embryos between stages 22-29 of HH. We have obtained a malformation percentage smaller than expected, on the basis of bibliographic data, so we now believe that hemodynamic factors, by themselves, don't play a role in the definitive morphogenesis and septation of great vessels and its main branches as important as believed until present time.