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Exp Neurol. 2018 Nov;309:14-22. doi: 10.1016/j.expneurol.2018.07.014. Epub 2018 Jul 25.

A genetic deficiency in folic acid metabolism impairs recovery after ischemic stroke.

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Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address:
Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
Nutrition Research Division, Health Canada, Ottawa, ON K1A 0K9, Canada.
Department of Biology Carleton University, Ottawa, ON K1S 5B6, Canada; Institute of Biochemistry, Carleton University, Ottawa, ON K1S 5B6, Canada.


Stroke is a leading cause of disability and death world-wide and nutrition is a modifiable risk factor for stroke. Metheylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the metabolism of folic acid, a B-vitamin. In humans, a polymorphism in MTHFR (677C→T) is linked to increased risk of stroke, but the mechanisms remain unknown. The Mthfr+/- mice mimic a phenotype described in humans at bp677. Using this mouse model, the aim of this study was to investigate the impact of MTHFR deficiency on stroke outcome. Male Mthfr+/- and wildtype littermate control mice were aged (~1.5-year-old) and trained on the single pellet reaching task. After which the sensorimotor cortex was then damaged using photothrombosis (PT), a model for ischemic stroke. Post-operatively, animals were tested for skilled motor function, and brain tissue was processed to assess cell death. Mthfr+/- mice were impaired in skilled reaching 2-weeks after stroke but showed some recovery at 5-weeks compared to wild types after PT damage. Within the ischemic brain, there was increased expression of active caspase-3 and reduced levels of phospho-AKT in neurons of Mthfr+/- mice. Recent data suggests that astrocytes may play a significant role after damage, the impact of MTHFR and ischemic investigated the impact of MTHFR-deficiency on astrocyte function. MTHFR-deficient primary astrocytes showed reduced cell viability after exposure to hypoxia compared to controls. Increased immunofluorescence staining of active caspase-3 and hypoxia-inducible factor 1-alpha were also observed. The data suggest that MTHFR deficiency decreases recovery after stroke by reducing neuronal and astrocyte viability.


Astrocytes; Ischemia; Methylenetetrahydrofolate reductase; Photothrombosis; Recovery

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