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bioRxiv · 10.1101/857938

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

Abato, J. E.·Moftah, M.·Cron, G. O.·Smith, P. D.·Jadavji, N. M.
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Abstract

ObjectiveElevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 CT) 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. MethodsIn 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. ResultsMthfr+/- 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-1) 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). ConclusionsOur 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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Abato, J. E., Moftah, M., Cron, G. O., Smith, P. D., Jadavji, N. M.. 2019-11-29. Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice. https://doi.org/10.1101/857938

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