TANSHINONE IIA PROTECTS DOPAMINERGIC NEURONS AGAINST 6-HYDROXYDOPAMINE-INDUCED NEUROTOXICITY THROUGH miR-153/NF-E2-RELATED FACTOR 2/ANTIOXIDANT RESPONSE ELEMENT SIGNALING PATHWAY
TANSHINONE IIA PROTECTS DOPAMINERGIC NEURONS AGAINST 6-HYDROXYDOPAMINE-INDUCED NEUROTOXICITY THROUGH miR-153/NF-E2-RELATED FACTOR 2/ANTIOXIDANT RESPONSE ELEMENT SIGNALING PATHWAY
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DOI：
10.1016/j.neuroscience.2015.06.030
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发表时间：
2015-09-10
期刊：
影响因子：
3.3
通讯作者：
Li, Z. A.
中科院分区：
文献类型：
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作者：
Zhang, X. S.;Ha, S.;Li, Z. A.
帕金森病（PD）是第二常见的进行性神经退行性疾病，其氧化应激增加，这是导致细胞死亡的潜在重要过程。丹参酮IIA（Tan IIA）是丹参中一种主要的生物活性二萜醌类化合物，在MPTP模型中具有抗炎作用。在这项研究中，我们发现Tan IIA通过激活NF-E2相关因子2（Nrf 2）-抗氧化反应元件（ARE）途径来防止黑质纹状体多巴胺能神经元的损失。Tan IIA处理SH-SY 5 Y细胞可减弱6-羟基多巴胺（6-OHDA）的细胞毒性，显著减少6-OHDA诱导的乳酸脱氢酶释放和活性氧的产生。进一步的研究表明，Tan IIA促进了Nrf 2在核内的积累，并与ARE序列结合，激活了ARE调控的基因，包括血红素加氧酶-1、谷氨酸半胱氨酸连接酶催化亚基（GCLC）和谷氨酸半胱氨酸连接酶修饰亚基（GCLM）。Tan IIA还保护线粒体膜电位免受损伤，减少细胞色素c从线粒体向细胞质的移位以及Caspase-9和Caspase-3的活化。此外，我们证明了上述作用是以Nrf 2依赖的方式进行的。进一步的研究表明，Tan IIA降低了靶向Nrf 2的3 '-UTR的6-OHDA对miR-153的增强作用，并抑制其表达和活化。此外，通过体内立体定位注射6-OHDA引起的神经变性也可以通过给予Tan IIA来改善。总之，我们的结果强烈表明，Tan IIA可能有利于治疗PD，也证实了靶向Nrf 2/ARE通路是一种有前途的PD治疗干预策略。(C)2015年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder with increased oxidative stress, the underlying vital process contributing to cell death. Tanshinone IIA (Tan IIA), a major bioactive diterpene quinone of Salva miltiorrhiza, had been proved effective in the MPTP model through its anti-inflammatory activity. Here in this research, we found that Tan IIA prevented the loss of nigrostriatal dopaminergic neurons by activating the NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. The cytotoxicity of 6-hydroxydopamine (6-OHDA) was attenuated by the treatment of Tan IIA in SH-SY5Y cells, which significantly reduced 6-OHDA-induced lactic dehydrogenase release and reactive oxygen species production. Further study indicated that Tan IIA contributed to the nuclear accumulation of Nrf2, which bound to the ARE sequence, and activated ARE-regulated genes, including heme oxygenase-1, glutamate cysteine ligase catalytic subunit (GCLC) and glutamate cysteine ligase modifier subunit (GCLM). Tan IIA also protected against damage to mitochondrial membrane potential, reduced the translocation of cytochrome c from the mitochondria to the cytoplasm and the activation of Caspase-9 and Caspase-3. Moreover, we demonstrated the above effects were performed in Nrf2-dependent manner. Further studies revealed that Tan IIA reduced the enhancement of miR-153 by 6-OHDA, which targeted the 3'-UTR of Nrf2, and suppressed its expression and activation. Additionally, neurodegeneration caused by in vivo stereotaxic injection of 6-OHDA could also be ameliorated by the administration of Tan IIA. Taken together, our results strongly suggest that Tan IIA may be beneficial for the treatment of PD, and also confirm that targeting the Nrf2/ARE pathway is a promising strategy for therapeutic intervention in PD. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.