One-carbon metabolism supplementation improves outcome after stroke in aged male MTHFR-deficient mice

Nafisa M. Jadavji; Hannah Mosnier; Erin Kelly; Kamaya Lawrence; Sarah Cruickshank; Sarah Stacey; Adelina McCall; Sandeep Dhatt; Erland Arning; Teodoro Bottiglieri; Patrice D. Smith

Neurobiology of Disease (Dec 2019)

One-carbon metabolism supplementation improves outcome after stroke in aged male MTHFR-deficient mice

Nafisa M. Jadavji,
Hannah Mosnier,
Erin Kelly,
Kamaya Lawrence,
Sarah Cruickshank,
Sarah Stacey,
Adelina McCall,
Sandeep Dhatt,
Erland Arning,
Teodoro Bottiglieri,
Patrice D. Smith

Affiliations

Nafisa M. Jadavji: Department of Neuroscience, Carleton University, Ottawa, ON, Canada; Department of Biomedical Sciences, Midwestern University, Phoenix, AZ, USA; Corresponding author at: Department of Biomedical Sciences, Midwestern University, 19555 N 59th Ave, Glendale, AZ 85308, USA.
Hannah Mosnier: Department of Neuroscience, Carleton University, Ottawa, ON, Canada
Erin Kelly: Department of Neuroscience, Carleton University, Ottawa, ON, Canada
Kamaya Lawrence: Department of Neuroscience, Carleton University, Ottawa, ON, Canada
Sarah Cruickshank: Department of Neuroscience, Carleton University, Ottawa, ON, Canada
Sarah Stacey: Department of Neuroscience, Carleton University, Ottawa, ON, Canada
Adelina McCall: Department of Neuroscience, Carleton University, Ottawa, ON, Canada
Sandeep Dhatt: Department of Neuroscience, Carleton University, Ottawa, ON, Canada
Erland Arning: Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA
Teodoro Bottiglieri: Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA
Patrice D. Smith: Department of Neuroscience, Carleton University, Ottawa, ON, Canada

Journal volume & issue: Vol. 132

Abstract

Read online

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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

About the journal

Abstract

Keywords