Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice. (4th March 2022)

• Record Type: Journal Article
• Authors: Abato, Jamie E.; Moftah, Mahira; Cron, Greg O.; Smith, Patrice D.; Jadavji, Nafisa M.
• Is Part Of: Nutritional neuroscience. Volume 25:Number 3(2022)
• Page Start: 558
• Page End: 566
• Publication Date: 2022-03-04
• Subjects: Ischemic stroke -- homocysteine -- methylenetetrahydrofolate reductase -- one-carbon metabolism -- antioxidant; Neuropharmacology -- Periodicals; Diet -- Periodicals; Diet therapy -- Periodicals; Nutrition -- Periodicals; 615.78
• DOI: 10.1080/1028415X.2020.1769412
• Languages: English
• ISSNs: 1028-415X

Abstract

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 for histological analysis. Results: Mthfr +/- animals used their non-impaired forepaw more 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) in neurons and astrocytes and neuronal superoxide dismutase 2 (SOD2) levels. Conclusions: Our results suggest that Mthfr +/- mice are more vulnerable to PT-induced stroke damage through the regulation of the cellular response. The increased antioxidant response we observed may be compensatory to the damage amount.