Quercetin Attenuates Manganese-Induced Neuroinflammation by Alleviating Oxidative Stress through Regulation of Apoptosis, iNOS/NF-κB and HO-1/Nrf2 Pathways.
Quercetin Attenuates Manganese-Induced Neuroinflammation by Alleviating Oxidative Stress through Regulation of Apoptosis, iNOS/NF-κB and HO-1/Nrf2 Pathways.
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DOI：
10.3390/ijms18091989
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发表时间：
2017-09-15
影响因子：
5.6
通讯作者：
Yoon H
中科院分区：
文献类型：
--
作者：
Bahar E;Kim JY;Yoon H
锰（Mn）是人体发育所必需的微量元素，并作为各种代谢反应的酶辅因子或激活剂。虽然微量的锰是必需的，但过量的锰暴露可导致人脑组织中的毒性积累，并导致类似于特发性帕金森病（PD）的锥体外系症状，称为锰中毒。槲皮素（QCT）已被证明在改变神经退行性疾病的进展中发挥重要作用，通过保护免受氧化应激。本研究旨在探讨QCT对锰所致神经毒性的保护作用及其机制。结果表明，Mn处理显著降低SK-N-MC细胞的细胞活力，并增加乳酸脱氢酶（LDH）的释放，而10和20 µg/mL的QCT预处理则减弱了该作用。与Mn单独组相比，QCT预处理显著减轻Mn诱导的氧化应激、线粒体功能障碍和细胞凋亡。同时，与Mn单独给药组相比，QCT预处理显著下调NF-κB，上调血红素加氧酶-1（HO-1）和Nrf 2蛋白。我们的结果表明，QCT对血液学参数的有益影响，对锰在大鼠脑。QCT能降低锰中毒大鼠体内活性氧（ROS）和蛋白质羰基水平，提高铜锌超氧化物歧化酶（SOD）活性。QCT给药通过抑制炎症标志物（如肿瘤坏死因子-α（TNF-α）、白细胞介素-1 β（IL-1β）、白细胞介素-6（IL-6）、环氧合酶-2（考克斯-2）和诱导型一氧化氮合酶（iNOS））的表达，显著降低Mn诱导的神经炎症。QCT降低了Mn升高的各种下游凋亡标志物的水平，包括Bax、细胞色素c、裂解的半胱天冬酶-3和聚合酶-1（PARP-1），而QCT处理上调了抗凋亡Bcl-2蛋白并防止Mn诱导的神经变性。此外，QCT（25和50毫克/公斤）锰暴露大鼠的管理显示，改善组织病理学改变相比，锰治疗的大鼠。此外，QCT给锰暴露的大鼠给药显示8-羟基-2 ′-脱氧鸟苷（8-OHdG）、Bax、活化的caspase-3和PARP-1免疫反应性显著降低。结果表明，QCT能有效抑制Mn诱导的SK-N-MC细胞凋亡和炎症反应，其机制可能与激活HO-1/Nrf 2和抑制NF-κB通路有关。
Manganese (Mn) is an essential trace element required for the development of human body and acts as an enzyme co-factor or activator for various reactions of metabolism. While essential in trace amounts, excessive Mn exposure can result in toxic accumulations in human brain tissue and resulting extrapyramidal symptoms called manganism similar to idiopathic Parkinson’s disease (PD). Quercetin (QCT) has been demonstrated to play an important role in altering the progression of neurodegenerative diseases by protecting against oxidative stress. This study aimed to investigate the protective effect of QCT on Mn-induced neurotoxicity and the underlying mechanism in SK-N-MC human neuroblastoma cell line and Sprague-Dawley (SD) male rat brain. The results showed that Mn treatment significantly decreased the cell viability of SK-N-MC cell and increased the release of lactate dehydrogenase (LDH), which was attenuated by QCT pretreatment at 10 and 20 µg/mL. Compared to the Mn alone group, QCT pretreatment significantly attenuated Mn-induced oxidative stress, mitochondrial dysfunction and apoptosis. Meanwhile, QCT pretreatment markedly downregulated the NF-κB but upregulated the heme oxygenase-1 (HO-1) and Nrf2 proteins, compared to the Mn alone group. Our result showed the beneficial effect of QCT on hematological parameters against Mn in rat brain. QCT decrease reactive oxygen species (ROS) and protein carbonyl levels and increased Cu/Zn-superoxide dismutase (SOD) activity induced in Mn-treated rats. QCT administration caused a significant reduction in the Mn-induced neuroinflammation by inhibiting the expression of inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). QCT lowered the Mn elevated levels of various downstream apoptotic markers, including Bax, cytochrome c, cleaved caspase-3 and polymerase-1 (PARP-1), while QCT treatment upregulated anti-apoptotic Bcl-2 proteins and prevented Mn-induced neurodegeneration. Furthermore, administration of QCT (25 and 50 mg/kg) to Mn-exposed rats showed improvement of histopathological alteration in comparison to Mn-treated rats. Moreover, administration of QCT to Mn-exposed rats showed significant reduction of 8-hydroxy-2′-deoxyguanosine (8-OHdG), Bax, activated caspase-3 and PARP-1 immunoreactivity. These results indicate that QCT could effectively inhibit Mn induced apoptosis and inflammatory response in SK-N-MC cells and SD rats, which may involve the activation of HO-1/Nrf2 and inhibition of NF-κB pathway.
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