Folic acid supplementation during pregnancy prevents cognitive impairments and BDNF imbalance in the hippocampus of the offspring after neonatal hypoxia-ischemia

J Nutr Biochem. 2018 Oct;60:35-46. doi: 10.1016/j.jnutbio.2018.06.008. Epub 2018 Jul 5.


Folic acid (FA) supplementation (400 μg/day) has been recommended during pregnancy to prevent neural tube defects. However, in some countries, flours are required to be fortified with FA, possibly increasing the levels of this vitamin in pregnant women. Our previous studies have evidenced a dual effect of the FA treatment in a rat model of neonatal hypoxia-ischemia (HI). Aiming to better correlate with humans, this paper evaluated the effects of two different levels of FA supplementation during pregnancy on memory parameters and neuronal survival and plasticity in the hippocampus of rats submitted to the neonatal HI. During pregnancy, female Wistar rats received one of these diets: standard (SD), supplemented with 2 mg/kg of FA or with 20 mg/kg of FA. At the 7th PND, rats suffered the HI procedure. At the 60th PND rats were evaluated in the open field, Morris water maze, novel-object recognition and inhibitory avoidance tasks. Furthermore, neuronal density, synaptophysin densitometry and BDNF concentration were assessed in the hippocampus. Both doses of FA prevented the HI-induced memory impairments. The supplementation reversed the BDNF late increase in the hippocampus of the HI rats, but did not inhibit the neuronal death. In conclusion, FA supplementation during pregnancy prevented memory deficits and BDNF imbalance after neonatal HI. These findings are particularly relevant because neuroprotection was achieved even in the high level of FA supplementation during pregnancy, indicating that this intervention would be considered secure for the offspring development.

Keywords: Behavior; Brain damage; Folate; Perinatal asphyxia; Vitamin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn*
  • Brain-Derived Neurotrophic Factor / analysis*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cognitive Dysfunction / etiology
  • Cognitive Dysfunction / prevention & control*
  • Dietary Supplements
  • Female
  • Folic Acid / administration & dosage*
  • Hippocampus / chemistry*
  • Hypoxia-Ischemia, Brain / complications*
  • Maternal-Fetal Exchange
  • Neuroprotective Agents
  • Pregnancy
  • Rats
  • Rats, Wistar


  • Brain-Derived Neurotrophic Factor
  • Neuroprotective Agents
  • Folic Acid