Ischemic Stroke Increases Protein Expression of the Folate Receptor and One-carbon Enzymes in Brain Tissue From Male and Female Patients

Stroke is the second most common cause of death worldwide and predominantly affects individuals over 65 years old. Its prevalence is projected to increase in parallel with the aging global population. Nutrition is a modifiable risk factor for ischemic stroke. Folates, B-vitamins and choline play a central role in one-carbon metabolism (1 C), which is a key metabolic network that integrates nutritional signals with biosynthesis, redox homeostasis, epigenetics, regulation of cell proliferation, and stress resistance. Using preclinical models, our research group has previously shown that deficiencies in 1 C lead to worse stroke outcomes. However, the impact of ischemic stroke on 1 C enzymes in human brain tissue remains unexplored. The objective of this study is to investigate whether ischemic stroke contributes to a change in the levels of 1 C enzymes after ischemic stroke in male and female patients. Cortical brain tissue sections from ischemic stroke patients and controls were stained for enzymes involved in 1 C. All tissue was co-stained with neuronal nuclei (NeuN) and DAPI (4',6-diamidino-2-phenylindole). The colocalization of all three markers was evaluated by two individuals who were masked to the experimental groups. Ischemic stroke increased neuronal levels of the folate receptor and 1 C enzymes, methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and serine hydroxy methyltransferase (SHMT). In male stroke brain tissue was observed to have increased levels of MTHFR, TS, and SHMT. Female brain tissue had increases in the folate receptor and TS. The results suggest that ischemic stroke leads to changes in neuronal levels of FR and 1 C enzymes levels in penumbra. Further clinical investigation is required to determine whether there is increase enzymatic activity and how 1 C is impacted in other cells within the brain, such as glial and endothelial cells.