Traumatic brain injury is a major cause of death and disability worldwide, affecting over 69 million individuals yearly. One-carbon metabolism has been shown to have beneficial effects after brain ...damage, such as ischemic stroke. However, whether increasing one-carbon metabolite vitamins impacts traumatic brain injury outcomes in patients requires more investigation. The aim of this review is to evaluate how one-carbon metabolites impact outcomes after the onset of traumatic brain injury. PubMed, Web of Science, and Google Scholar databases were searched for studies that examined the impact of B-vitamin supplementation on traumatic brain injury outcomes. The search terms included combinations of the following words: traumatic brain injury, dietary supplementation, one-carbon metabolism, and B-vitamins. The focus of each literature search was basic science data. The year of publication in the literature searches was not limited. Our analysis of the literature has shown that dietary supplementation of B-vitamins has significantly improved the functional and behavioral recovery of animals with traumatic brain injury compared to controls. However, this improvement is dosage-dependent and is contingent upon the onset of supplementation and whether there is a sustained or continuous delivery of vitamin supplementation post-traumatic brain injury. The details of supplementation post-traumatic brain injury need to be further investigated. Overall, we conclude that B-vitamin supplementation improves behavioral outcomes and reduces cognitive impairment post-traumatic brain injury in animal model systems. Further investigation in a clinical setting should be strongly considered in conjunction with current medical treatments for traumatic brain injury-affected individuals.
Abstract Folates are B-vitamins that play an important role in brain function. Dietary and genetic deficiencies in folate metabolism result in elevated levels of homocysteine which have been linked ...to increased risk of developing a stroke. Reducing levels of homocysteine before or after a stroke through B-vitamin supplementation has been a focus of many clinical studies, however, the results remain inconsistent. Animal model systems provide a powerful mechanism to study and understand functional impact and mechanisms through which supplementation affects stroke recovery. The aim of this study was to understand the role of B-vitamins in stroke pathology using in vivo and in vitro mouse models. The first objective assessed the impact of folate deficiency prior to ischemic damage followed by B-vitamins and choline supplementation. Ischemic damage targeted the sensorimotor cortex. C57Bl/6 wild-type mice were maintained on a folic acid deficient diet for 4 weeks prior to ischemic damage to increased levels of plasma homocysteine, a risk factor for stroke. Post-operatively mice were placed on a B-vitamin and choline supplemented diet for a period of four weeks, after which motor function was assessed in mice using the rotarod, ladder beam and forepaw asymmetry tasks. The second objective was to determine how a genetic deficiency in methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in folate metabolism, increases vulnerability to stroke. Primary cortical neurons were isolated from Mthfr+/+ , Mthfr+/− and Mthfr−/− embryos and were exposed to in vitro models of stroke which include hypoxia or oxygen glucose deprivation. Cell viability was measured 24-h after exposure stroke like conditions in vitro . In supplemented diet mice, we report improved motor function after ischemic damage compared to mice fed a control diet after ischemic damage. Within the perilesional cortex, we show enhanced proliferation, neuroplasticity and anti-oxidant activity in mice fed the supplemented diet. A genetic MTHFR deficiency resulted in neurodegeneration after exposure to in vitro models of stroke, by activating apoptosis promoting p53-dependent mechanisms. These results suggest that one-carbon metabolism plays a significant role in recovery after stroke and MTHFR deficiency contributes to poor recovery from stroke.
Maternal dietary levels of one-carbon (1C) metabolites (folic acid and choline) during pregnancy play a vital role in neurodevelopment. However, the impact of maternal dietary deficiencies on ...offspring stroke outcomes later in life remains undefined. The aim of this study was to investigate the role of maternal dietary deficiencies in folic acid and choline on ischemic stroke outcomes in middle-aged offspring. Female mice were maintained on either a control or deficient diet prior to and during pregnancy and lactation. At 10 months of age ischemic stroke was induced in male and female offspring. Stroke outcome was assessed by measuring motor function and brain tissue. There was no difference in offspring motor function; however, sex differences were present. In brain tissue, maternal dietary deficiency increased ischemic damage volume and offspring from deficient mothers had reduced neurodegeneration and neuroinflammation within the ischemic region. Furthermore, there were changes in plasma 1C metabolites as a result of maternal diet and sex. Our data indicate that maternal dietary deficiencies do not impact offspring behavior after ischemic stroke but do play a role in brain histology and one-carbon metabolite levels in plasma. Additionally, this study demonstrates that the sex of mice plays an important role in stroke outcomes.
Folic acid, a B vitamin, is vital for early neurodevelopment and is well known for its protective effect against neural tube defects. Various national health agencies worldwide recommend that women ...of childbearing age take approximately 0.4 to 1 mg of supplemental folic acid daily to reduce the risk of neural tube defects in offspring. Several countries have tried to promote folic acid intake through mandatory fortification programs to reduce neural tube defects. Supplementation combined with mandatory fortification of foods has led to high levels of folic acid and related metabolites in women of childbearing age. Recent studies have reported that oversupplementation, defined as exceeding either the recommended dietary allowance or the upper limit of the daily reference intake of folic acid, may have negative effects on human health. This review examines whether maternal oversupplementation with folic acid affects the neurodevelopment of offspring. Data from animal studies suggest there are behavioral, morphological, and molecular changes in the brain of offspring. Additional studies are required to determine both the dosage of folic acid and the timing of folic acid intake needed for optimal neurodevelopment in humans.
Elevated plasma homocysteine levels have been identified as a significant, independent risk factor for the development of cognitive decline including Alzheimer's disease. While several studies have ...explored the link between homocysteine and disease risk, the associations have not been entirely clear. Elevated levels of homocysteine serve as a disease marker and understanding the underlying cause of these increased levels (e.g., dietary or genetic deficiency in one-carbon metabolism, 1C) will provide valuable insights into neurological disease risk and outcomes. Previous cell culture experiments investigating the mechanisms involved used ultra-high levels of homocysteine that are not observed in human patients. These studies have demonstrated the negative impacts of ultra-high levels of homocysteine can have on for example proliferation of neuroprogenitor cells in the adult hippocampus, as well as triggering neuronal apoptosis through a series of events, including DNA damage, PARP activation, NAD depletion, mitochondrial dysfunction, and oxidative stress. The aim of this mini-review article will summarize the literature on deficiencies in 1C and how they contribute to disease risk and outcomes and that homocysteine is a marker of disease.
Ischemic stroke results in disability and mortality worldwide. Nutrition is a modifiable risk factor for stroke. For example, deficiencies in one-carbon metabolism have been linked to increased risk ...of stroke through elevated levels of homocysteine. Some countries world-wide fortify their diets with folates to prevent neural tube defects, but deficiencies in other one-carbon metabolites, such as vitamin B12 and choline are still present in many populations. The aim of this review is to understand the current evidence on how dietary supplementation by nutrients which modulate one-carbon metabolism impact stroke outcome.
The results from clinical studies evaluating lowering homocysteine through B-vitamin supplementation on stroke risk remain unclear. Other clinical and preclinical studies have shown increasing dietary intake of one-carbon metabolism has some benefit on stroke outcome. Preclinical studies have shown that increased levels of nutrients which modulate one-carbon metabolism help facilitate recovery in damage models of the central nervous system. One the mechanisms driving these changes is neuroplasticity.
The data suggest that increasing dietary nutrients that modulate one-carbon metabolites in patients that are at a higher risk for and suffer from central nervous system diseases, such as stroke, could benefit in addition to other therapies.
Many postdoctoral researchers apply for faculty positions knowing relatively little about the hiring process or what is needed to secure a job offer. To address this lack of knowledge about the ...hiring process we conducted a survey of applicants for faculty positions: the survey ran between May 2018 and May 2019, and received 317 responses. We analyzed the responses to explore the interplay between various scholarly metrics and hiring outcomes. We concluded that, above a certain threshold, the benchmarks traditionally used to measure research success - including funding, number of publications or journals published in - were unable to completely differentiate applicants with and without job offers. Respondents also reported that the hiring process was unnecessarily stressful, time-consuming, and lacking in feedback, irrespective of outcome. Our findings suggest that there is considerable scope to improve the transparency of the hiring process.
The prevalence of stroke increases with age and the ability to absorb all nutrients from our diets decreases with age. Nutrition is a modifiable risk factor for stroke, which is a leading cause of ...death and disability in world-wide. Deficiencies in one‑carbon metabolism, including in methyltetrahydrofolate reductase (MTHFR), have been linked to increased risk of stroke. The Mthfr+/− mice mouse model mimic the phenotype of the MTHFR677C➔T polymorphism, such as elevated levels of homocystine. Using this mouse model, the aim of this study was to investigate the impact of dietary supplementation with 5-methylTHF, vitamin B12, and choline after ischemic stroke. Male Mthfr+/− and wildtype littermate control mice were aged (~1.5-year-old) and were placed on control diet (CD) 4-weeks prior to sensorimotor cortex damage using photothrombosis (PT), a model for ischemic stroke. Post-operatively, one group of Mthfr+/− and wildtype littermate mice were placed on 5-methylTHF, vitamin B12, and choline supplemented diet (SD). Four weeks after PT and SD motor function was assessed using the accelerating rotarod, forepaw asymmetry, and ladder beam walking tasks. Total homocysteine and cysteine levels were measured in blood. Brain tissue was processed to assess lesion volume and investigate biochemical and molecular changes. After PT and SD, Mthfr+/− mice were able to stay on the accelerating rotarod longer and used their impaired forepaw to explore more when compared to CD animals. Furthermore, total homocysteine levels in plasma and lesion volume were reduced in Mthfr+/+ and Mthfr+/− SD mice. Within the damage site, there were reduced levels of apoptotic cell death and increased neuroprotective cellular response in the brains of SD treated Mthfr+/− mice. This study reveals a critical role for one‑carbon supplementation, with 5-methylTHF, vitamin B12, and choline, in supporting improvement after ischemic stroke damage.
•In Mthfr+/−mice supplementation reduced motor impairment after stroke.•tHcy levels and lesion volumes were reduced in supplemented animals.•In brain tissue, there were reduced levels of active caspase-3 of supplemented mice.•HIF-α levels were increased in ischemic core of Mthfr+/− supplemented mice.
PDF
