One-carbon (1C) metabolism is a metabolic network that is centered on folate, a B vitamin; it integrates nutritional signals with biosynthesis, redox homeostasis, and epigenetics. This metabolic pathway also reduces levels of homocysteine, a non-protein amino acid. High levels of homocysteine are linked to increased risk of hypoxic events, such as stroke. Several preclinical studies have suggested that 1C metabolism can impact stroke outcome, but the clinical data are unclear. The objective of this paper was to review preclinical and clinical research to determine whether 1C metabolism has an antioxidant role on stroke. To accomplish the objective, we searched for publications using the following medical subject headings (MeSH) keywords: antioxidants, hypoxia, stroke, homocysteine, one-carbon metabolism, folate, methionine, and dietary supplementation of one-carbon metabolism. Both pre-clinical and clinical studies were retrieved and reviewed. Our review of the literature suggests that deficiencies in 1C play an important role in the onset and outcome of stroke. Dietary supplementation of 1C provides beneficial effects on stroke outcome. For stroke-affected patients or individuals at high risk for stroke, the data suggest that nutritional modifications in addition to other therapies could be incorporated into a treatment plan.

A vitamin B12 deficiency (vit. B12 def.) is common in the elderly, because of changes in metabolism. Clinical studies have reported that a vit. B12 def. results in worse outcome after stroke, and the mechanisms through which a vit. B12 def. changes the brain requires further investigation. This study investigated the role of vit. B12 def. on stroke outcome and mechanisms using aged female mice. Eighteen-month-old females were put on a control or vit. B12 def. diet for 4 weeks, after which an ischemic stroke was induced in the sensorimotor cortex. After damage, motor function was measured, the animals were euthanized, and tissues were collected for analysis. Vit. B12 def. animals had increased levels of total homocysteine in plasma and liver, and choline levels were also increased in the liver. Vit. B12 def. animals had larger damage volume in brain tissue and more apoptosis. The cecum tissue pathway analysis showed dysfunction in B12 transport. The analysis of mitochondrial metabolomics in brain tissue showed reduced levels of metabolites involved in the TCA cycle in vit. B12 def. animals. Motor function after stroke was impaired in vit. B12 def. animals. A dietary vit. B12 def. impairs motor function through increased apoptosis and changes in mitochondrial metabolism in brain tissue.

The global population is aging and the prevalence of age-related diseases, such as stroke, is predicted to increase. A vitamin B12 deficiency (vit. B12 def.) is common in the elderly, because of changes in metabolism. Clinical studies have reported that a vit. B12 def results in worse outcome after stroke, the mechanisms through which a vit. B12 def. changes the brain requires further investigation. This study investigated the role of vit. B12 def. on stroke outcome and mechanisms using aged female mice. Eighteen month old females were put on a control or vit. B12 def. diet for four weeks, after which an ischemic stroke was induced in the sensorimotor cortex. After damage, motor function was measured and animals were euthanized and tissues were collected for analysis. Vit. B12 def. animals had increased levels of total homocysteine in plasma and liver, choline levels were also increased in the liver. Vit. B12 def. animals had larger damage volume in brain tissue and more apoptosis. In the cecum, changes in creatinine and methylmalonic acid were observed in vit. B12 def. animals, pathway analysis showed dysfunction in B12 transport. Analysis of mitochondrial metabolomics in brain tissue showed reduced levels of metabolites involved in the TCA cycle in vit. B12 def animals. Meanwhile, pathway analysis showed significant, widespread dysfunction in phenylalanine, tyrosine, and tryptophan biosynthesis. Motor function after stroke was impaired in vit. B12 def. animals. A dietary vitamin B12 deficiency impairs motor function through increased apoptosis and changes in mitochondrial metabolism in brain tissue.

Background Recent evidence suggests that sex plays a role when there are deficiencies in one-carbon metabolism, however, the impact on brain tissue remains unknown. Objective The aim of the study was to examine the impact of sex differences and dietary folic acid deficiency on brain tissue in adult mice. Methods Male and female C57Bl/6J mice were placed on a folic acid deficient (FD) or control diet (CD) at six weeks of age. Mice were maintained on these diets for six months, after which animals were euthanized and brain tissue and serum were collected for analysis. Serum folate levels were measured. In brain tissue, hippocampal volume and morphology including Cornu Ammonis 1 and 3 (CA1; CA3), and dentate gyrus thickness were measured. Apoptosis within the hippocampus was assessed using active caspase-3 immunofluorescence staining. Additionally, cortical acetylcholine metabolism was measured in brain tissue using immunofluorescence staining of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT). Results Male and female FD mice had reduced serum levels of folate. Both males and females maintained on a FD showed a decrease in the thickness of the hippocampal CA3 region. Interestingly, there was a sex difference in the levels of apoptosis within the CA1 region of the hippocampus. In cortical tissue, there were increased levels of neuronal ChAT and reduced levels of AChE in FD females and male mice. Conclusions The results indicated that FD impacts hippocampal morphology through increased apoptosis and changes acetylcholine metabolism within the cortex. The data from our study indicate a sex difference in apoptosis and differences in hippocampal morphology and choline metabolism as a result of dietary folic acid deficiency.