title: B-vitamin and choline supplementation increases neuroplasticity and recovery after stroke.
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 4weeks 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.
authors.affiliation: Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada; Department of Experimental Neurology, Center for Stroke Research Berlin, Charité University Medicine Berlin, Germany. Electronic address: nafisa.jadavji@mail.mcgill.ca.
authors.forename: Nafisa M
authors.initials: NM
authors.lastname: Jadavji
authors.affiliation: Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Emmerson
authors.affiliation: Nutrition Research Division, Health Canada, Ottawa, ON K1A 0K9, Canada.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: MacFarlane
authors.affiliation: Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Institute of Biochemistry, Carleton University, Ottawa, ON K1S 5B6, Canada.
authors.forename: William G
authors.initials: WG
authors.lastname: Willmore
authors.affiliation: Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Smith
mesh_terms: D000818:Animals; D002794:Choline / Q000008:administration & dosage*; D019587:Dietary Supplements; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D011897:Random Allocation; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D020521:Stroke / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D014803:Vitamin B Complex; C000609029:MTHFR protein, mouse; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002794:Choline
keywords: Cerebral ischemia; Cortical plasticity; Folate; Homocysteine; Methylenetetrahydrfolate reductase