Gestational folic acid supplementation does not affects the maternal behavior and the early development of rats submitted to neonatal hypoxia‐ischemia but the high supplementation impairs the dam's memory and the Na⁺, K⁺ ‐ ATPase activity in the pup's hippocampus

Abstract

Folic acid (FA) is a B‐complex vitamin important to the development of the fetus, being supplemented during pregnancy. Our recent findings showed that gestation supplementation (normal and excess doses) prevented the cognitive deficits and BDNF imbalance in adult rats that were submitted to neonatal hypoxia‐ischemia (HI). To better understand this protective effect, the present study aimed to evaluate whether FA supplementation could be related to (1) maternal behavior, memory and Na+, K+ ‐ ATPase activity in the hippocampus of the dams; (2) on somatic growth, early neurobehavioral development and Na+, K+ ‐ ATPase activity in the hippocampus of the offspring; and (3) the effects of this supplementation in pups submitted to neonatal HI. Pregnant Wistar rats were divided into three groups, according to the diet they received during gestation: standard diet (SD), supplemented with 2 mg/kg of FA (FA2 – normal dose) and supplemented with 20 mg/kg of FA (FA20 –excessive dose). At the 7th PND pups were submitted to the Levine‐Vannucci model of HI. During weaning the maternal behavior, the somatic growth and the neurobehavior development of pups were assessed. After weaning, the memory of the dams (by the Ox‐maze task) and the Na+, K+ ‐ ATPase activity in the hippocampus of both dams and offspring were evaluated. Considering the dams (1), both doses of FA did not alter the maternal behavior or the Na+, K+ ‐ ATPase activity in the hippocampus, but a memory deficit was observed in the high FA‐supplemented mothers. Considering the offspring (2), both FA doses did not affect the somatic growth or the neurobehavior development, but the FA20 pups had a decreased Na+, K+ ‐ ATPase activity in the hippocampus. The FA supplementation did not change the parameters evaluated in the HI rats (3) and did not prevent the decreased Na+, K+ ‐ ATPase activity in the hippocampus of the HI pups. These results indicate that normal FA supplementation dose does not influence the maternal behavior and memory and does not impact on the offspring early development in rats. Further studies are needed to confirm the effects of the high FA supplementation dose in the dams’ memory and in the Na+, K+ ‐ ATPase activity in the hippocampus of the offspring.

Does folic acid supplementation have a positive effect on improving memory? A systematic review and meta-analysis of randomized controlled trials

“…Also, high levels of folic acid can decrease the activity of the Na+, K+-ATPase enzyme. The proper functioning of this enzyme is related to the memory and learning process, because this enzyme continuously interacts with N-methyl-D-aspartate (NMDA) receptor which is located in the synaptic regions and it has an important role in the memory process ( Vieira Carletti et al, 2016 ; Deniz et al, 2018 ).…”

Dose-Dependent Neuroprotective Effects of Bovine Lactoferrin Following Neonatal Hypoxia–Ischemia in the Immature Rat Brain

“…There is robust preclinical evidence that supports the neuroprotective properties of nutritional interventions during pregnancy counteracting HI brain damage. The use of folic acid [24,25], docosahexaenoic acid [26,27] resveratrol [28], vitamin A [29], melatonin [30], as well as dietary interventions using pomegranate juice [31] or broccoli sprouts [32], and others, may represent a safe and inexpensive strategy for the prevention and treatment of neonatal HI damage. Lactoferrin (Lf) is an iron-binding glycoprotein found in breast milk [33][34][35].…”