Protective Effect of Dimethyl Fumarate on an Oxidative Stress Model Induced by Sodium Nitroprusside in Mice.
Protective Effect of Dimethyl Fumarate on an Oxidative Stress Model Induced by Sodium Nitroprusside in Mice.
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DOI：
10.1248/bpb.b16-00134
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发表时间：
2016-06
影响因子：
2
通讯作者：
T. Kume;A. Suenaga;Yasuhiko Izumi;A. Akaike
中科院分区：
文献类型：
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作者：
T. Kume;A. Suenaga;Yasuhiko Izumi;A. Akaike
最近的报道表明，富马酸二甲酯（DMF）可以预防脑出血引起的脑损伤，这种有益作用是通过核红细胞2 p45相关因子-2-抗氧化反应元件（Nrf2-ARE）途径介导的。然而，Nrf2-ARE通路激活的下游机制尚不清楚。在这里，我们通过硝普钠（SNP）诱导的氧化应激体内模型和大鼠原代纹状体培养来研究DMF的保护作用。口服DMF可预防snp诱导的运动功能障碍。预先给药DMF (60-200 mg/kg) 24小时，剂量依赖性地保护纹状体注射SNP引起的脑损伤。接下来，我们利用大鼠原代纹状体细胞培养研究DMF对氧化应激的保护作用及其机制。用DMF（10µM）处理纹状体细胞可明显防止过氧化氢诱导的细胞毒性。在体外实验中，DMF对氧化应激的保护作用被血红素氧化酶-1抑制剂原卟啉锌IX所抑制，而被谷胱甘肽合成抑制剂丁硫氨酸亚砜胺所抑制。这些结果表明，血红素加氧酶-1的激活在DMF的保护作用中起重要作用。
Recent reports have shown that dimethyl fumarate (DMF) prevents brain damage induced by intracerebral hemorrhage and this beneficial effect is mediated by the nuclear erythroid 2 p45-related factor-2-antioxidant response element (Nrf2-ARE) pathway. However, the downstream mechanism underlying the activation of the Nrf2-ARE pathway is unclear. Here, we investigated the protective effect of DMF using an in vivo model of oxidative stress induced by sodium nitroprusside (SNP) and rat primary striatal cultures. Oral administration of DMF prevented SNP-induced motor dysfunction. Pre-administration of DMF (60-200 mg/kg) for 24 h dose-dependently protected against brain damage induced by the striatal injection of SNP. Next, we investigated the protective effect and mechanism of DMF against oxidative stress using rat primary striatal cell cultures. Treatment of striatal cells with DMF (10 µM) markedly prevented hydrogen peroxide-induced cytotoxicity. The protective effect of DMF against oxidative stress in vitro was inhibited by zinc protoporphyrin IX, an inhibitor of heme oxygenase-1, but not by buthionine sulfoximine, an inhibitor of glutathione synthesis. These results suggest that the activation of heme oxygenase-1 plays an important role in the protective effect of DMF.