Investigating the Preventative Potential of Bioactive Folates in Mitigating Spina Bifida with Hydrocephalus Comorbidity

Abstract

Folates are crucial in the entire process of pregnancy, and their deficiency can result in congenital diseases such as spina bifida (SB), which are often comorbid with hydrocephalus (HC). Maternal folic acid supplements can precipitate the incidence of hydrocephalus in neonates, and any fault in the folic acid metabolism can prevent the growing embryo from receiving the bioactive folates required for cellular processes. This highlights a need to look for something more promising than folic acid supplementations. We aimed to identify and compare the preventative impact of synthetic and bioactive maternal folate supplements on CNS in an animal model of SB-HC comorbidity generated through valproic acid. Three maternal folate supplements were selected: folic acid (synthetic folate), folinic acid (bioactive folate), and folinic acid+ 5-methyltetrahydrofolate (5-mTHF) (mixture of bioactive folates). The gross appearance and morphological study of the fetuses revealed hydrocephalus precipitation in the folic acid group, which was best prevented by the treatment of folinic acid+5-mTHF. Cerebral folate expression was increased, and methylation levels were decreased in the folic acid group. This indicates that the folates have not been utilized in the DNA and RNA methylation, which is necessary for cerebral development. The activity of cerebral folate receptor alpha was also reduced in the folic acid group. The best preventative effects regarding folate utilization, methylation, and folate receptor activity were observed in the case of folinic acid+5-mTHF. The data indicates that bioactive folates, especially a mixture of folinic acid and 5-mTHF, outperform synthetic folate in the prevention of SB-HC comorbidity.