Nucleotide precursors prevent folic acid-resistant neural tube defects in the mouse

• Published in: Brain (London, England : 1878) Vol. 136; no. Pt 9; pp. 2836 - 2841
• Main Authors: LEUNG, Kit-Yi, DE CASTRO, Sandra C. P, SAVERY, Dawn, COPP, Andrew J, GREENE, Nicholas D. E
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-09-2013
• Subjects: Animals; Biological and medical sciences; Body Patterning - drug effects; Body Patterning - physiology; Cell Proliferation - drug effects; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Embryo, Mammalian; Female; Folic Acid - adverse effects; Folic Acid - metabolism; Histones - metabolism; Litter Size - drug effects; Male; Maternal Exposure; Medical sciences; Mice; Mice, Mutant Strains; Neural Tube Defects - drug therapy; Neural Tube Defects - genetics; Neural Tube Defects - prevention & control; Neurology; Original; Pregnancy; Purine Nucleosides - therapeutic use; Pyrimidine Nucleosides - therapeutic use; Statistics, Nonparametric; Thymidine - therapeutic use; Embryo; Nervous system diseases; curly tail; Diseases of the osteoarticular system; Rodentia; neural tube defects; Spine disease; Congenital disease; Precursor; Folic acid; Neural tube defect; Spina bifida; Vertebrata; Mammalia; Mouse; Malformation; Animal; nucleotides; embryo; spina bifida
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awt209

Closure of the neural tube during embryogenesis is a crucial step in development of the central nervous system. Failure of this process results in neural tube defects, including spina bifida and anencephaly, which are among the most common birth defects worldwide. Maternal use of folic acid supplements reduces risk of neural tube defects but a proportion of cases are not preventable. Folic acid is thought to act through folate one-carbon metabolism, which transfers one-carbon units for methylation reactions and nucleotide biosynthesis. Hence suboptimal performance of the intervening reactions could limit the efficacy of folic acid. We hypothesized that direct supplementation with nucleotides, downstream of folate metabolism, has the potential to support neural tube closure. Therefore, in a mouse model that exhibits folic acid-resistant neural tube defects, we tested the effect of specific combinations of pyrimidine and purine nucleotide precursors and observed a significant protective effect. Labelling in whole embryo culture showed that nucleotides are taken up by the neurulating embryo and incorporated into genomic DNA. Furthermore, the mitotic index was elevated in neural folds and hindgut of treated embryos, consistent with a proposed mechanism of neural tube defect prevention through stimulation of cellular proliferation. These findings may provide an impetus for future investigations of supplemental nucleotides as a means to prevent a greater proportion of human neural tube defects than can be achieved by folic acid alone.