Department of Biomedical Sciences, Midwestern University, Glendale, AZ, USA.
Department of Neuroscience, Carleton University, Ottawa, Canada.
Nutr Neurosci. 2022 Mar;25(3):558-566. doi: 10.1080/1028415X.2020.1769412. Epub 2020 May 25.
Elevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase ( 677 C→T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of -adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that mice, which model the 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. In the present study, three-month-old male and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, imaging was performed using T2-weighted MRI, and brain tissue was collected for histological analysis. 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 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. Our results suggest that 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.
同型半胱氨酸浓度升高是中风的一个风险因素。亚甲基四氢叶酸还原酶（MTHFR）中的一个常见基因多态性（677C→T）导致同型半胱氨酸水平升高。MTHFR 在合成 - 腺苷甲硫氨酸（SAM）中起着关键作用，SAM 是一种全局甲基供体。我们之前的工作表明，模拟人类 677C→T 多态性的 小鼠对缺血性损伤更敏感。本研究旨在探讨 MTHFR 缺乏在缺血性中风损伤背景下改变大脑的细胞机制。在本研究中，3 个月大的雄性 小鼠和野生型同窝小鼠接受光血栓形成（PT）损伤。PT 损伤后 4 周，对动物进行行为测试，使用 T2 加权 MRI 进行成像，并收集脑组织进行组织学分析。与野生型同窝小鼠相比， 小鼠使用未受损的前爪更多地探索圆筒，并且损伤体积更大。在 小鼠的脑组织中，损伤半球内的蛋氨酸腺苷转移酶 IIα（MAT2A）蛋白水平降低，非损伤半球内的缺氧诱导因子 1α（HIF-1α）水平升高。损伤部位的抗氧化反应增加，神经元和星形胶质细胞中的核因子红细胞 2 相关因子 2（Nrf2）和神经元超氧化物歧化酶 2（SOD2）水平升高。我们的结果表明， 小鼠通过调节细胞反应更容易受到 PT 诱导的中风损伤。我们观察到的增加的抗氧化反应可能是对损伤量的代偿。
