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.

Additional Metadata
Keywords Astrocytes, Ischemia, Methylenetetrahydrofolate reductase, Photothrombosis, Recovery
Persistent URL dx.doi.org/10.1016/j.expneurol.2018.07.014
Journal Experimental Neurology
Citation
Jadavji, N.M. (Nafisa M.), Emmerson, J.T. (Joshua T.), Shanmugalingam, U. (Ushananthini), McFarlane, A, Willmore, W, & Smith, P.D. (Patrice D.). (2018). A genetic deficiency in folic acid metabolism impairs recovery after ischemic stroke. Experimental Neurology, 309, 14–22. doi:10.1016/j.expneurol.2018.07.014