Liu Yizhi, Qiu Jiaoxue, Wang Zhong, You Wanchun, Wu Lingyun, Ji Chengyuan, Chen Gang
Department of Neurosurgery and Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
J Neurosurg. 2015 Oct;123(4):915-23. doi: 10.3171/2014.11.JNS132348. Epub 2015 Jan 23.
Oxidative stress and the inflammatory response are thought to promote brain damage in the setting of subarachnoid hemorrhage (SAH). Previous reports have shown that dimethylfumarate (DMF) can activate the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2-antioxidant-responsive element (Keap1-Nrf2-ARE) system in vivo and in vitro, which leads to the downregulation of oxidative stress and inflammation. The aim of this study was to evaluate the potential neuroprotective effect of DMF on SAH-induced brain injury in rats.
Rats were subjected to SAH by the injection of 300 μl of autologous blood into the chiasmatic cistern. Rats in a DMF-treated group were given 15 mg/kg DMF twice daily by oral gavage for 2 days after the onset of SAH. Cortical apoptosis, neural necrosis, brain edema, blood-brain barrier impairment, learning deficits, and changes in the Keap1-Nrf2-ARE pathway were assessed.
Administration of DMF significantly ameliorated the early brain injury and learning deficits induced by SAH in this animal model. Treatment with DMF markedly upregulated the expressions of agents related to Keap1-Nrf2-ARE signaling after SAH. The inflammatory response and oxidative stress were downregulated by DMF therapy.
DMF administration resulted in abatement of the development of early brain injury and cognitive dysfunction in this prechiasmatic cistern SAH model. This result was probably mediated by the effect of DMF on the Keap1-Nrf2-ARE system.
氧化应激和炎症反应被认为在蛛网膜下腔出血（SAH）情况下会促进脑损伤。先前的报道表明，富马酸二甲酯（DMF）在体内和体外均可激活 Kelch 样 ECH 相关蛋白 1-核因子红系 2 相关因子 2-抗氧化反应元件（Keap1-Nrf2-ARE）系统，从而导致氧化应激和炎症的下调。本研究的目的是评估 DMF 对大鼠 SAH 诱导的脑损伤的潜在神经保护作用。
通过向视交叉池注射 300 μl 自体血使大鼠发生 SAH。DMF 治疗组的大鼠在 SAH 发作后 2 天内每天经口灌胃给予 15 mg/kg DMF，共 2 天。评估皮质凋亡、神经坏死、脑水肿、血脑屏障损伤、学习缺陷以及 Keap1-Nrf2-ARE 通路的变化。
在该动物模型中，给予 DMF 可显著改善 SAH 诱导的早期脑损伤和学习缺陷。DMF 治疗显著上调了 SAH 后与 Keap1-Nrf2-ARE 信号相关因子的表达。DMF 治疗下调了炎症反应和氧化应激。
在该视交叉池前 SAH 模型中，给予 DMF 可减轻早期脑损伤和认知功能障碍的发展。这一结果可能是由 DMF 对 Keap1-Nrf2-ARE 系统的作用介导的。
