Journal article
Mahira Moftah, G. Cron, Joshua T. Emmerson, Bill Willmore, Patrice D. Smith, N. Jadavji
Current Developments in Nutrition, 2019
Current Developments in Nutrition, 2019
Semantic Scholar
DOI
PubMed
Cite
Cite
APA
Click to copy
Moftah, M., Cron, G., Emmerson, J. T., Willmore, B., Smith, P. D., & Jadavji, N. (2019). MTHFR-deficiency Increases Ischemic Damage Through Reduced Neuronal and Astrocytes Viability and Changes in the Cellular Response (P01-020-19). Current Developments in Nutrition.
Chicago/Turabian
Click to copy
Moftah, Mahira, G. Cron, Joshua T. Emmerson, Bill Willmore, Patrice D. Smith, and N. Jadavji. “MTHFR-Deficiency Increases Ischemic Damage Through Reduced Neuronal and Astrocytes Viability and Changes in the Cellular Response (P01-020-19).” Current Developments in Nutrition (2019).
MLA
Click to copy
Moftah, Mahira, et al. “MTHFR-Deficiency Increases Ischemic Damage Through Reduced Neuronal and Astrocytes Viability and Changes in the Cellular Response (P01-020-19).” Current Developments in Nutrition, 2019.
BibTeX Click to copy
@article{mahira2019a,
title = {MTHFR-deficiency Increases Ischemic Damage Through Reduced Neuronal and Astrocytes Viability and Changes in the Cellular Response (P01-020-19).},
year = {2019},
journal = {Current Developments in Nutrition},
author = {Moftah, Mahira and Cron, G. and Emmerson, Joshua T. and Willmore, Bill and Smith, Patrice D. and Jadavji, N.}
}
Abstract
Objectives Stroke is a leading cause of disability and death world-wide. Increased levels of homocysteine are associated with risk for stroke. Metheylenetetrahydrofolate reductase (MTHFR) generates methyl groups to aid in the metabolism of homocysteine. A polymorphism in MTHFR (677C→T) has been identified in 5-15% of North American and European populations. Individuals with the TT genotype have elevated homocysteine concentrations and have increased risk of stroke. Using the MTHFR mouse model, the objective of this study was to investigate the mechanisms through which MTHFR deficiency may increase the risk of stroke.
Methods We isolated primary neurons and astrocytes cells from MTHFR-deficient mice and exposed cells to hypoxia for 6 hours. Twenty-four hours after damage, we measured cell viability. In vivo, using aged (∼1.5-year-old) male Mthfr +/- and wildtype littermate controls, the sensorimotor cortex was damaged using the photothrombosis model to induce ischemic stroke. Post-operatively, animals were tested on skilled motor function, and brain tissue was processed for analysis. Additionally, in adult male mice using MRI we measured lesion volume two and four weeks after damage.
Results Primary neurons and astrocytes from MTHFR-deficient embryos showed reduced cell viability through increased trypan blue staining and MTT release. In vivo, aged Mthfr +/- mice were impaired in skilled motor function after damage. Using MRI, adult Mthfr +/- brains were more severely damaged compared to wild-type littermates. In vitro and in vivo, we observed increased apoptosis in Mthfr +/- animals. Furthermore, methionine adenosyltransferase II alpha (MAT2A) protein levels were increased in the stroke hemisphere of wild-type mice. In the non-PT hemisphere of Mthfr +/- mice there was an increase in hypoxia induced factor 1 alpha (HIF-1α) protein and growth differentiation factor 11 (GDF11).
Conclusions Together, our results suggest that Mthfr +/- mice are more vulnerable to ischemic stroke damage. This is through reducing neuronal and astrocyte viability after damage, as well as changes in methylation and cellular response.
Funding Sources This research was funded by the Natural Sciences and Engineering Research Council, Council of Ontario Universities, and Fonds de la recherché en santé Québec (FRSQ).