Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice
Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice
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DOI：
10.1089/ars.2016.6905
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发表时间：
2017-11-10
影响因子：
6.6
通讯作者：
Kanthasamy, Anumantha G.
中科院分区：
文献类型：
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作者：
Langley, Monica;Ghosh, Anamitra;Kanthasamy, Anumantha G.
目的：帕金森病（PD）是一种以进行性运动障碍和多巴胺能神经元变性为特征的神经退行性疾病。由许多遗传和环境因素引起的线粒体功能障碍和氧化应激在PD的神经变性中起作用。通过选择性地敲除多巴胺能神经元中的线粒体转录因子A（TFAM），转基因MitoPark小鼠重现了该疾病的许多特征，包括进行性运动缺陷、神经元损失和蛋白质内含物。在本研究中，我们评估了一种新的神经靶向抗氧化剂，Mito-apocynin，在MitoPark小鼠和细胞培养模型的神经炎症和线粒体dysfunction.Results模型的神经保护效果：口服Mito-apocynin（10 mg/kg，每周三次）显示出良好的中枢神经系统生物利用度和显著改善运动活动和协调在MitoPark小鼠。重要的是，Mito-apocynin也部分减弱了MitoPark小鼠的严重黑质纹状体变性。机制研究表明，Mito-apo可改善线粒体功能，抑制NOX 2活化、氧化损伤和神经炎症。创新：MitoPark转基因小鼠模型中鉴定的Mito-apocynin的性质，有力支持Mito-apocynin作为一种可行的神经保护和抗神经炎症药物治疗PD的潜在临床应用，与传统治疗方法相比。总的来说，我们的数据表明，第一次，一种新的口服活性夹竹桃麻素衍生物改善行为，炎症和神经退行性过程中的严重进行性多巴胺能神经退行性模型的PD。
Aims: Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor deficits and degeneration of dopaminergic neurons. Caused by a number of genetic and environmental factors, mitochondrial dysfunction and oxidative stress play a role in neurodegeneration in PD. By selectively knocking out mitochondrial transcription factor A (TFAM) in dopaminergic neurons, the transgenic MitoPark mice recapitulate many signature features of the disease, including progressive motor deficits, neuronal loss, and protein inclusions. In the present study, we evaluated the neuroprotective efficacy of a novel mitochondrially targeted antioxidant, Mito-apocynin, in MitoPark mice and cell culture models of neuroinflammation and mitochondrial dysfunction.Results: Oral administration of Mito-apocynin (10mg/kg, thrice a week) showed excellent central nervous system bioavailability and significantly improved locomotor activity and coordination in MitoPark mice. Importantly, Mito-apocynin also partially attenuated severe nigrostriatal degeneration in MitoPark mice. Mechanistic studies revealed that Mito-apo improves mitochondrial function and inhibits NOX2 activation, oxidative damage, and neuroinflammation.Innovation: The properties of Mito-apocynin identified in the MitoPark transgenic mouse model strongly support potential clinical applications for Mito-apocynin as a viable neuroprotective and anti-neuroinflammatory drug for treating PD when compared to conventional therapeutic approaches.Conclusion: Collectively, our data demonstrate, for the first time, that a novel orally active apocynin derivative improves behavioral, inflammatory, and neurodegenerative processes in a severe progressive dopaminergic neurodegenerative model of PD.