Dimethyl Fumarate Attenuates Neuroinflammation and Neurobehavioral Deficits Induced by Experimental Traumatic Brain Injury
Dimethyl Fumarate Attenuates Neuroinflammation and Neurobehavioral Deficits Induced by Experimental Traumatic Brain Injury
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DOI：
10.1089/neu.2017.5260
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发表时间：
2018-04-17
影响因子：
4.2
通讯作者：
Esposito, Emanuela
中科院分区：
文献类型：
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作者：
Casili, Giovanna;Campolo, Michela;Esposito, Emanuela
创伤性脑损伤（TBI）是一种严重的神经病理学，可引起继发性损伤机制，包括缺血性、炎症性和细胞毒性过程之间的动态相互作用。富马酸酯（FAE）在神经炎症和毒性氧化应激的临床前模型中显示出有益作用，因此本工作的目的是评估富马酸二甲酯（DMF）在受控皮质撞击（CCI）诱导的TBI小鼠模型中的潜在有益作用。CCI后1 h和4 h，小鼠经口给予1、10和30 mg/kg剂量的DMF。我们进行了组织学，分子和免疫组织化学分析脑外伤后24小时的半暗区CCI。DMF处理显著降低了组织学损伤和行为障碍，减少了神经变性，如神经元丢失评估、Fluoro-Jade C和TUNEL染色所证明;此外，DMF处理阻断了细胞凋亡过程，增加了受损皮质中B细胞淋巴瘤2（Bcl-2）的表达。此外，DMF处理上调抗氧化剂Kelch样ECH相关蛋白1/核因子红细胞2相关因子途径，诱导锰超氧化物歧化酶和血红素加氧酶-1活化，并减少4-羟基-2-壬烯醛染色。此外，通过调节NF-κ B通路，DMF处理通过调节神经元型一氧化氮合酶、白细胞介素1、肿瘤坏死因子、环氧合酶2和髓过氧化物酶活性，降低离子化钙结合衔接子分子1和神经胶质细胞酸性蛋白表达，降低炎症严重程度。我们的研究结果支持了DMF可能是脑外伤后有效的神经保护剂的论点，值得进一步研究。
Traumatic brain injury (TBI) is a serious neuropathology that causes secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory, and cytotoxic processes. Fumaric acid esters (FAEs) showed beneficial effects in pre-clinical models of neuroinflammation and toxic oxidative stress, so the aim of the present work was to evaluate the potential beneficial effects of dimethyl fumarate (DMF), the most pharmacologically effective molecules among the FAEs, in a mouse model of TBI induced by controlled cortical impact (CCI). Mice were administered DMF orally at the doses of 1, 10, and 30 mg/kg 1 h and 4 h after CCI. We performed histological, molecular, and immunohistochemistry analysis on the traumatic penumbral areas of the brain 24 h after CCI. DMF treatment notably reduced histological damage and behavioral impairments, reducing neurodegeneration as evidenced by assessments of neuronal loss, Fluoro-Jade C, and TUNEL staining; also, treatment with DMF blocked the apoptosis process increasing B-cell lymphoma 2 (Bcl-2) expression in injured cortex. Further, DMF treatment up-regulated antioxidant Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor pathway, inducing activation of manganese superoxide dismutase and heme-oxygenase-1 and reducing 4-hydroxy-2-nonenal staining. Also, regulating the NF-kappa B pathway, DMF treatment decreased the severity of inflammation through a modulation of neuronal nitric oxide synthase, interleukin 1, tumor necrosis factor, cyclooxygenase 2, and myeloperoxidase activity, reducing ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein expression. Our results support the thesis that DMF may be an effective neuroprotectant after brain trauma and warrants further study.