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Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice

Jamie E. Abato, Mahira Moftah, Greg O. Cron, Patrice D. Smith, View ORCID ProfileNafisa M. Jadavji
doi: https://doi.org/10.1101/857938
Jamie E. Abato
1Department of Biomedical Sciences, Midwestern University, Glendale, US
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Mahira Moftah
2Department of Neuroscience, Carleton University, Ottawa, Canada
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Greg O. Cron
3Department of Radiology, University of Ottawa
4The Ottawa Hospital Research Institute
5Department of Medical Imaging, The Ottawa Hospital
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Patrice D. Smith
2Department of Neuroscience, Carleton University, Ottawa, Canada
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Nafisa M. Jadavji
1Department of Biomedical Sciences, Midwestern University, Glendale, US
2Department of Neuroscience, Carleton University, Ottawa, Canada
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  • ORCID record for Nafisa M. Jadavji
  • For correspondence: njadav@midwestern.edu
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Abstract

Objective Elevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 C➔T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of S-adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that Mthfr+/− mice, which model the MTHFR polymorphism in humans, are more vulnerable to ischemic damage. The aim of this study was to investigate the cellular mechanisms by which the MTHFR-deficiency changes the brain in the context of ischemic stroke injury.

Methods In the present study, three-month-old male Mthfr+/− and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, in vivo imaging was performed using T2-weighted MRI, and brain tissue was collected.

Results Mthfr+/− animals used their non-impaired forepaw more during to explore the cylinder and had a larger damage volume compared to wild-type littermates. In brain tissue of Mthfr+/− mice methionine adenosyltransferase II alpha (MAT2A) protein levels were decreased within the damage hemisphere and increased levels in hypoxia induced factor 1 alpha (HIF-1α) in non-damage hemisphere. There was an increased antioxidant response in the damage site as indicated by higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide dismutase 2 (SOD2).

Conclusions Our results suggest that Mthfr+/− mice are more vulnerable to PT-induced stroke damage through regulation of the cellular response. The increased antioxidant response we observed may be compensatory to the damage amount.

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  • Revisions to manuscript text.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 09, 2019.
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Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice
Jamie E. Abato, Mahira Moftah, Greg O. Cron, Patrice D. Smith, Nafisa M. Jadavji
bioRxiv 857938; doi: https://doi.org/10.1101/857938
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Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice
Jamie E. Abato, Mahira Moftah, Greg O. Cron, Patrice D. Smith, Nafisa M. Jadavji
bioRxiv 857938; doi: https://doi.org/10.1101/857938

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