右美托咪定激活Nrf2-ARE信号通路对创伤性脑损伤的抗氧化作用

目的探讨右美托咪定（DEX）对创伤性脑损伤（TBI）模型大鼠的神经保护作用、氧自由基清除及脑组织红系衍生的核因子相关因子2（Nrf2）-抗氧化反应原件（ARE）信号通路参与的机制。 方法选择健康成年雄性大鼠体重300~350 g构建TBI模型，将60只SD大鼠分为3组：假手术组（Sham组）、TBI组和TBI＋DEX组，每组20只。其中Sham组仅去除脑颅骨不打砸，TBI组和DEX组均采用改良自由落体装置制备TBI模型，随后在造模后1 h分别给予等量0.9%NaCl和DEX（100 μg/kg）处理。通过采用改良神经功能缺损评分（mNSS）评价神经功能，脑组织干湿重称量法评价脑水肿。使用酶活试剂盒检测损伤24 h后抗氧化酶超氧化物歧化酶（SOD）和丙二醛（MDA）。最后使用免疫印迹试验（Western blot）和实时定量基因扩增荧光检测系统（RT-qPCR）的方法检测Nrf2-ARE信号通路及其下游分子血红素加氧酶1（HO-1）、醌氧化还原酶1（NQO-1）的表达水平，表达情况。 结果与TBI组相比，DEX组mNSS评分显著降低（P<0.05），DEX组能够明显减少脑水肿（P<0.05）；DEX组能够明显增加抗氧化酶SOD活性，降低氧化应激产物MDA的水平（P<0.05）。 结论DEX能够激活Nrf2-ARE信号通路诱导下游抗氧化/解毒酶等靶基因的表达，从而抑制氧化应激损伤发挥神经保护作用。

Antioxidant effects of dexmedetomidine in traumatic brain injury rats by activating Nrf2-ARE pathway

ObjectiveTo investigate the neuroprotective effect of dexmedetomidine in traumatic brain injury (TBI) rat model and the relationship with clearance of oxygen free radicals and the erythroid-derived nuclear factor-related factor 2 (Nrf2)-antioxidant/electrophilic response element (ARE) signal pathway. MethodsHealthy adult male SD rats weighing 300-350 g were selected to construct a TBI model. Sixty rats were divided into three groups: sham operation group (Sham group), traumatic brain injury group (TBI group) and dexmedetomidine (TBI+ DEX group) group. In Sham group, only brain skulls were removed. In TBI and TBI+ DEX groups, the rats were all prepared with a modified free-fall device to induce traumatic brain injury . Rats in TBI and TBI+ DEX groups received same amount of saline and dexmedetomidine (100 μg/kg) treatment 1 h after the onset of TBI respectively. Neurological function was evaluated by modified neurological deficit scores (mNss), and cerebral edema was evaluated by brain dry-wet weight method. The enzyme activity kit was used to detect the antioxidant enzymes SOD and MDA after 24 hours of injury. Finally, Western blot, RT-qPCR and immunofluorescence methods were used to detect the expression level of Nrf2-ARE signaling pathway and its downstream molecules HO-1, NQO-1expression. ResultsCompared with TBI group, mNss scores in DEX group were significantly lower (P<0.05). DEX could significantly reduce brain edema (P<0.05); DEX could significantly reduce the levels of antioxidant enzyme SOD and oxidative stress product MDA (P<0.05). ConclusionDEX can activate Nrf2-ARE signaling pathway to induce the expression of target genes such as antioxidant/detoxifying enzymes downstream to inhibit oxidative stress and exert neuroprotection.