Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Department of Nutriology, Tianjin Children's Hospital, Tianjin, 300074, China.
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin, 300070, China.
Neurochem Int. 2021 Jul;147:105065. doi: 10.1016/j.neuint.2021.105065. Epub 2021 May 1.
Ischemic stroke represents a major cause of mortality worldwide. An elevated level of homocysteine (Hcy) is recognized as a powerful risk factor of ischemic stroke. We previously reported that Hcy induces cytotoxicity and proliferation inhibition in neural stem cells (NSCs) derived from the neonatal rat hippocampus in vitro. However, the toxic potential of Hcy on NSCs and its underlying mechanisms are not entirely clear in ischemic brain. Since DNA methylation is critical for establishing the diverse cell fates in the central nervous system, we hypothesized that negative effect of Hcy (an intermediate in the one-carbon metabolism) on neurogenesis might be link to DNA methylation in ischemic stroke. In our study, the rats in Hcy intervention group were intraperitoneally injected with 2% Hcy solution (5 mL/kg/d) for 7 consecutive days before MCAO surgery until they were sacrificed. Our study indicated that Hcy inhibited NSCs self-renewal capacity, which was exhibited by lowering the number of DCX/BrdU and NeuN/BrdU in ischemic brain hippocampus. A reduction in the activity of the DNA methyltransferases (DNMTs), total methylation level and the number of 5mC/NeuN and DCX/5mC cells was observed in Hcy-treated ischemic brains. Additionally, Hcy also induced an increase in S-adenosylhomocysteine (SAH), and a decrease in the ratio of S-adenosylmethionine (SAM) to SAH. These results suggest that the alterations in DNA methylation may be an important mechanism by which Hcy inhibits neurogenesis after stroke. Hcy-induced DNA hypomethylation may be mainly caused by a reduction in the DNMT activity which is regulated by the concentrations of SAM and SAH. Maintaining normal DNA methylation by lowering Hcy level may possess therapeutic potential for promoting neurological recovery and reconstruction after stroke.
缺血性中风是全球范围内主要的死亡原因之一。同型半胱氨酸（Hcy）水平升高被认为是缺血性中风的一个强有力的危险因素。我们之前的研究表明，Hcy 在体外诱导新生大鼠海马来源的神经干细胞（NSCs）的细胞毒性和增殖抑制。然而，Hcy 对 NSCs 的毒性潜力及其在缺血性脑内的潜在机制尚不完全清楚。由于 DNA 甲基化对于中枢神经系统中不同细胞命运的建立至关重要，我们假设 Hcy（一碳代谢的中间产物）对神经发生的负面影响可能与缺血性中风中的 DNA 甲基化有关。在我们的研究中，Hcy 干预组的大鼠在 MCAO 手术前连续 7 天每天腹腔注射 2% Hcy 溶液（5ml/kg/d），直到处死。我们的研究表明，Hcy 抑制了 NSCs 的自我更新能力，这表现为缺血性海马脑内 DCX/BrdU 和 NeuN/BrdU 的数量减少。在 Hcy 处理的缺血性脑内观察到 DNA 甲基转移酶（DNMTs）的活性降低、总甲基化水平降低以及 5mC/NeuN 和 DCX/5mC 细胞的数量减少。此外，Hcy 还诱导 S-腺苷同型半胱氨酸（SAH）增加，S-腺苷甲硫氨酸（SAM）与 SAH 的比值降低。这些结果表明，DNA 甲基化的改变可能是 Hcy 抑制中风后神经发生的重要机制。Hcy 诱导的 DNA 低甲基化可能主要是由于 DNMT 活性降低所致，而 DNMT 活性受 SAM 和 SAH 浓度的调节。通过降低 Hcy 水平维持正常的 DNA 甲基化可能对促进中风后神经功能恢复和重建具有治疗潜力。
