Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease.
Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease.
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DOI：
10.1111/jnc.14033
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发表时间：
2017-06
影响因子：
4.7
通讯作者：
Kanthasamy AG
中科院分区：
文献类型：
--
作者：
Ay M;Luo J;Langley M;Jin H;Anantharam V;Kanthasamy A;Kanthasamy AG
槲皮素是植物中主要的类黄酮之一，最近被报道对神经退行性过程具有神经保护作用。然而，由于控制这些作用的分子信号机制尚不清楚，我们评估了槲皮素在多巴胺能神经元模型中对神经保护信号事件的影响，并进一步测试了其在mitpark转基因帕金森病小鼠模型中的功效。Western blotting分析显示，槲皮素显著诱导MN9D多巴胺能神经元细胞中两种主要细胞存活激酶PKD1和Akt的活化。此外，药物抑制或siRNA敲低PKD1可阻断Akt的激活，这表明PKD1在槲皮素介导的神经保护信号传导中是Akt的上游调节剂。槲皮素还增强了CREB磷酸化和CREB靶基因BDNF的表达。qRT-PCR、Western blot分析、mtDNA含量分析和MitoTracker实验结果显示槲皮素增强了线粒体的生物发生。槲皮素还能提高线粒体生物能量能力，保护MN9D细胞免受6-羟基多巴胺诱导的神经毒性。为了进一步评估槲皮素对帕金森病线粒体功能障碍的神经保护作用，我们使用了进行性多巴胺能神经退行性mitpark转基因帕金森病小鼠模型。口服槲皮素可显著逆转MitoPark小鼠的行为缺陷、纹状体多巴胺消耗和TH神经元细胞丢失。总之，我们的研究结果表明槲皮素激活PKD1-Akt细胞存活信号轴，并表明进一步探索槲皮素作为治疗PD的有前途的神经保护剂可能会带来临床益处。我们研究了槲皮素在帕金森病（PD）进行性神经退行性小鼠模型中的神经保护作用的分子机制。槲皮素处理通过上调PGC-1α和TFAM，激活PKD1和Akt促生存激酶，促进线粒体生物发生。总的来说，我们的数据表明槲皮素是一种治疗帕金森病的有前途的神经保护剂。
Quercetin, one of the major flavonoids in plants, has been recently reported to have neuroprotective effects against neurodegenerative processes. However, since the molecular signaling mechanisms governing these effects are not well clarified, we evaluated quercetin’s effect on the neuroprotective signaling events in dopaminergic neuronal models and further tested its efficacy in the MitoPark transgenic mouse model of Parkinson’s disease (PD). Western blotting analysis revealed that quercetin significantly induced the activation of two major cell survival kinases, protein kinase D1 (PKD1) and Akt in MN9D dopaminergic neuronal cells. Furthermore, pharmacological inhibition or siRNA knockdown of PKD1 blocked the activation of Akt, suggesting that PKD1 acts as an upstream regulator of Akt in quercetin-mediated neuroprotective signaling. Quercetin also enhanced CREB phosphorylation and expression of the CREB target gene BDNF. Results from qRT-PCR, Western blot analysis, mtDNA content analysis, and MitoTracker assay experiments revealed that quercetin augmented mitochondrial biogenesis. Quercetin also increased mitochondrial bioenergetics capacity and protected MN9D cells against 6-OHDA-induced neurotoxicity. To further evaluate the neuroprotective efficacy of quercetin against the mitochondrial dysfunction underlying PD, we used the progressive dopaminergic neurodegenerative MitoPark transgenic mouse model of PD. Oral administration of quercetin significantly reversed behavioral deficits, striatal dopamine depletion, and TH neuronal cell loss in MitoPark mice. Together, our findings demonstrate that quercetin activates PKD1-Akt cell survival signaling axis and suggest that further exploration of quercetin as a promising neuroprotective agent for treating PD may offer clinical benefits. We investigated the molecular mechanisms governing the neuroprotective effect of quercetin in a progressive neurodegenerative mouse model of Parkinson’s disease (PD). Quercetin treatment activated PKD1 and Akt pro-survival kinases and enhanced mitochondrial biogenesis by up-regulating PGC-1α and TFAM. Collectively, our data suggest that quercetin is a promising neuroprotective agent for treating PD.
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影响因子：
4.8
作者：
Durgadoss, Lalitha;Nidadavolu, Prakash;Ravindranath, Vijayalakshmi
通讯作者：
Ravindranath, Vijayalakshmi
影响因子：
7.4
作者：
Dranka, Brian P.;Hill, Bradford G.;Darley-Usmar, Victor M.
通讯作者：
Darley-Usmar, Victor M.
影响因子：
4.4
作者：
Boots, Agnes W.;Wilms, Lonneke C.;Haenen, Guido R. M. M.
通讯作者：
Haenen, Guido R. M. M.
影响因子：
3.6
作者：
Egert, Sarah;Bosy-Westphal, Anja;Mueller, Manfred J.
通讯作者：
Mueller, Manfred J.
DOI：
10.1186/1550-2783-10-3
发表时间：
2013-01-14
影响因子：
5.1
作者：
Casuso RA;Martínez-Amat A;Martínez-López EJ;Camiletti-Moirón D;Porres JM;Aranda P
通讯作者：
Aranda P