Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways.
Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways.
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DOI：
10.1016/j.freeradbiomed.2015.12.027
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发表时间：
2016-03
影响因子：
7.4
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Cheng T;Wang W;Li Q;Han X;Xing J;Qi C;Lan X;Wan J;Potts A;Guan F;Wang J
创伤性脑损伤（TBI）是一种严重的健康问题，可导致残疾、功能障碍甚至死亡，目前尚无有效的治疗方法。一种名为（−）-表儿茶素（EC）的脑渗透性类黄酮调节氧化还原/氧化应激，并已被证明对人类的血管和认知功能以及啮齿动物的缺血性和出血性中风有益。在这里，我们研究了EC是否能够保护脑免受TBI诱导的小鼠脑损伤，如果是这样，它是否通过调节NF-E2相关因子（Nrf 2）通路发挥神经保护作用。我们使用受控皮质撞击模型来模拟TBI。在TBI后3小时口服EC，然后每24小时一次，持续3或7天。我们评估了病变体积、脑水肿、白色损伤、神经功能缺损、认知能力和情感样行为、中性粒细胞浸润、活性氧（ROS）和各种损伤相关蛋白标志物。Nrf 2敲除小鼠用于确定EC处理后Nrf 2信号传导途径的作用。在野生型小鼠中，EC显著减少了病变体积、水肿和细胞死亡，并在第3天和第28天改善了神经功能; EC给药也改善了认知能力和抑郁样行为。此外，EC减少TBI后的白色物质损伤、血红素氧合酶-1表达和三价铁沉积。这些变化伴随着中性粒细胞浸润和氧化损伤的衰减，基质金属蛋白酶9的活性降低，Keap 1表达降低，Nrf 2核积累增加，超氧化物歧化酶1和醌1的表达增加。然而，EC并没有显着减少病变体积或改善神经功能缺损Nrf 2敲除小鼠TBI后。我们的研究结果表明，EC通过激活Nrf 2通路，抑制血红素加氧酶-1蛋白表达，减少铁沉积来保护TBI脑。后两种效应可能代表了该TBI模型中的Nrf 2独立机制。
Traumatic brain injury (TBI), which leads to disability, dysfunction, and even death, is a prominent health problem worldwide with no effective treatment. A brain-permeable flavonoid named (−)-epicatechin (EC) modulates redox/oxidative stress and has been shown to be beneficial for vascular and cognitive function in humans and for ischemic and hemorrhagic stroke in rodents. Here we examined whether EC is able to protect the brain against TBI-induced brain injury in mice and if so, whether it exerts neuroprotection by modulating the NF-E2-related factor (Nrf2) pathway. We used the controlled cortical impact model to mimic TBI. EC was administered orally at 3 h after TBI and then every 24 h for either 3 or 7 days. We evaluated lesion volume, brain edema, white matter injury, neurologic deficits, cognitive performance and emotion-like behaviors, neutrophil infiltration, reactive oxygen species (ROS), and a variety of injury-related protein markers. Nrf2 knockout mice were used to determine the role of the Nrf2 signaling pathway after EC treatment. In wild-type mice, EC significantly reduced lesion volume, edema, and cell death and improved neurologic function on days 3 and 28; cognitive performance and depression-like behaviors were also improved with EC administration. In addition, EC reduced white matter injury, heme oxygenase-1 expression, and ferric iron deposition after TBI. These changes were accompanied by attenuation of neutrophil infiltration and oxidative insults, reduced activity of matrix metalloproteinase 9, decreased Keap 1 expression, increased Nrf2 nuclear accumulation, and increased expression of superoxide dismutase 1 and quinone 1. However, EC did not significantly reduce lesion volume or improve neurologic deficits in Nrf2 knockout mice after TBI. Our results show that EC protects the TBI brain by activating the Nrf2 pathway, inhibiting heme oxygenase-1 protein expression, and reducing iron deposition. The latter two effects could represent an Nrf2-independent mechanism in this model of TBI.