DECIPHERING THE POTENTIAL FAULT IN HEPATIC FOLATE METABOLISM IN A RAT MODEL OF SPINA BIFIDA WITH HYDROCEPHALUS COMORBIDITY

Abstract

Folate is an important B vitamin that is required for nucleotide production, DNA and RNA methylation, and one-carbon metabolism. Folates are important for the management and prevention of neural tube defects (NTDs), including hydrocephalus (HC) and spina bifida (SB). Generating a rat model of SB-HC co-morbidity, induced by Valproic acid (VPA). This research evaluates the effectiveness of synthetic and bioactive forms of folate supplementation strategies. Folic acid lowers the risk of spina bifida, it may exacerbate hydrocephalus. VPA disrupts folate metabolism enzymes, increasing neural tube defects (NTDs) risk. Bioactive folate forms, like folinic acid and 5-mTHF, offer a more promising therapeutic solution for mitigating these defects. The most promising outcomes were obtained when folinic acid and 5-mTHF were combined. In the rat model, these treatments improved brain development, cortical thickness, and gross morphology, greatly reducing symptoms of both disorders. This shows that when co-morbid diseases are present, bioactive forms of folate are more successful in treating NTDs than synthetic folic acid as hydrocephalus is seen to be precipitated in the case of the folic acid group. Localized methylation decrease was obsereved through analysis highlighting localized error in spine region. The study also shows that the folic acid group had a build-up of folate, while the sick group had a deficiency. The diseased group's decreased 5-methylcytosine (5-mC) levels, changed DNA methylation patterns disrupted folate receptor (FR-α) highlight the epigenetic impacts of folate deficency. Treatments with bioactive folate restored hepatic folate levels and normalised DNA methylation, so correcting these epigenetic changes. The results highlight the importance of bioactive folates instead of synthetic folic acid, implying improved therapeutic advantages for folate metabolism impairment and systematic error caused by VPA. Bioactive folate supplementation effectively mitigates NTD symptoms and corrects VPA-induced epigenetic errors, offering superior benefits over synthetic folic acid in therapy.