BACKGROUND Oxidative stress and inflammatory pathways are involved in migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of the most pharmacologically effective molecules among the fumaric acid esters (FAEs), dimethyl fumarate, nuclear factor E2-related factor 2/antioxidant response element (Nrf-2/ARE) pathway-mediated, in regulating the hypersensitivity in a mouse model of nitroglycerine (NTG)-induced migraine. METHODS Mice were orally administered with DMF at the doses of 10, 30, and 100 mg/kg, 5 min after NTG intraperitoneal injections. We performed histological and molecular analysis on the whole brain and behavioral tests after 4 h by NTG-migraine induction. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) subunit p65, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), inducible nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Nrf-2, manganese superoxide dismutase (Mn-SOD), and heme-oxygenase-1 (HO-1) were detected by Western blot. Tail flick, hot plate, orofacial formalin, and photophobia tests were used to evaluate migraine-like pain and migraine-related light sensitivity. Moreover, we evaluate Nrf-2-dependent mechanism by the in vitro stimulation of cells extracted by trigeminal ganglia with diethylenetriamine/nitric oxide (DETA/NO), a nitric oxide (NO) donor. The cells were pre-treated with DMF and an antagonist of Nrf-2, trigonelline (TR) 2 h before DETA/NO stimulation. RESULTS DMF treatment notably reduced histological damage as showed by cresyl violet staining; also, regulating both NF-κB and Nrf-2 pathway, DMF treatment decreased the severity of inflammation and increased the protective antioxidant action. Moreover, the headache was significantly reduced. The protective effect of DMF treatment, via Nrf-2, was confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline. Cytotoxicity, iNOS, and MnSOD expression were evaluated. CONCLUSION These results provided the evidence that DMF, by Nrf-2 modulation, has a protective effect on central sensitization induced by NTG, suggesting a new insight into the potential application of DMF as novel candidates in drug development for migraine.

中文翻译：

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富马酸二甲酯减轻了小鼠硝酸甘油（NTG）诱导的偏头痛。

背景技术氧化应激和炎性途径参与偏头痛，并且内源性抗氧化剂防御系统在预防偏头痛的痛觉过敏中起作用。在这项研究中，我们旨在评估富马酸酯（FAE），富马酸二甲酯，核因子E2相关因子2 /抗氧化反应元件（Nrf-2 / ARE）途径介导的最药理学有效分子的作用，在调节硝酸甘油（NTG）诱导的偏头痛的小鼠模型中的超敏反应中。方法腹膜内注射NTG 5分钟后，分别以10、30和100 mg / kg的剂量口服DMF小鼠。NTG-偏头痛诱导后4小时，我们对整个大脑进行了组织学和分子分析，并进行了行为测试。活化B细胞核因子κ轻链增强子（NF-кB）p65的表达，κ光多肽基因增强子的核因子在B细胞抑制剂α（IκBα）中的表达，诱导型亚硝酸盐合酶（iNOS）， Western印迹检测到环氧合酶2（COX-2），Nrf-2，锰超氧化物歧化酶（Mn-SOD）和血红素加氧酶-1（HO-1）。甩尾，热板，口部福尔马林和畏光测试用于评估偏头痛样疼痛和偏头痛相关的光敏感性。此外，我们通过体外刺激三叉神经节提取的细胞与一氧化氮（NO）供体的二乙烯三胺/一氧化氮（DETA / NO）来评估Nrf-2依赖性机制。在DETA / NO刺激前2小时，将细胞用DMF和Nrf-2的拮抗剂Trigonelline（TR）进行预处理。结果甲酚紫染色显示，DMF处理可显着减少组织学损害；此外，DMF治疗通过调节NF-κB和Nrf-2途径，降低了炎症的严重性并增强了保护性抗氧化作用。此外，头痛明显减轻。在体外研究中，通过穿山甲碱抑制Nrf-2，证实了DMF通过Nrf-2的保护作用。评估细胞毒性，iNOS和MnSOD表达。结论这些结果提供了证据，即通过Nrf-2调节的DMF对NTG诱导的中枢敏化具有保护作用，这表明对DMF作为偏头痛药物开发的新候选药物的潜在应用有了新的认识。DMF治疗可降低炎症的严重程度，并增强保护性抗氧化作用。此外，头痛明显减轻。在体外研究中，通过穿山甲林抑制Nrf-2，证实了DMF通过Nrf-2的保护作用。评估细胞毒性，iNOS和MnSOD表达。结论这些结果提供了证据，即通过Nrf-2调节的DMF对NTG诱导的中枢敏化具有保护作用，这表明对DMF作为偏头痛药物开发的新候选药物的潜在应用有了新的认识。DMF治疗可降低炎症的严重程度，并增强保护性抗氧化作用。此外，头痛明显减轻。在体外研究中，通过穿山甲林抑制Nrf-2，证实了DMF通过Nrf-2的保护作用。评估细胞毒性，iNOS和MnSOD表达。结论这些结果提供了证据，即通过Nrf-2调节的DMF对NTG诱导的中枢敏化具有保护作用，这表明对DMF作为偏头痛药物开发的新候选药物的潜在应用有了新的认识。可以通过trigonelline抑制Nrf-2。评估细胞毒性，iNOS和MnSOD表达。结论这些结果提供了证据，即通过Nrf-2调节的DMF对NTG诱导的中枢敏化具有保护作用，这表明对DMF作为偏头痛药物开发的新候选药物的潜在应用有了新的认识。可以通过trigonelline抑制Nrf-2。评估细胞毒性，iNOS和MnSOD表达。结论这些结果提供了证据，即通过Nrf-2调节的DMF对NTG诱导的中枢敏化具有保护作用，这表明对DMF作为偏头痛药物开发的新候选药物的潜在应用有了新的认识。