Therapeutic approaches to mitochondrial dysfunction in Parkinson's disease
Therapeutic approaches to mitochondrial dysfunction in Parkinson's disease
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DOI：
10.1016/s1353-8020(09)70812-0
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发表时间：
2009-12-01
影响因子：
4.1
通讯作者：
Beal, M. Flint
中科院分区：
文献类型：
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作者：
Beal, M. Flint
来自人类死后脑组织和遗传分析的大量证据，以及神经变性动物模型的生化和病理研究表明，线粒体功能障碍是帕金森病（PD）的一个关键病理机制。线粒体功能障碍导致氧化应激、线粒体DNA损伤、线粒体DNA缺失、线粒体形态改变、线粒体裂变和融合改变，最终导致神经元死亡。因此，针对线粒体功能障碍和氧化损伤的治疗方法在帕金森病中具有很大的前景。许多靶向能量代谢的药物目前正在PD的治疗试验中。肌酸和辅酶Q10 （CoQ10）正在III期临床试验中进行测试。此外，动物模型的临床前研究显示了线粒体靶向抗氧化剂和SS肽的有效性。增加抗氧化防御的一个很有希望的方法是通过转录增加Nrf2/ARE通路的活性，该通路激活抗炎和抗氧化基因的转录。包括萝卜硫素、姜黄素和三萜在内的许多药物已被证明可以激活这一途径并产生神经保护作用。最后，新发现的治疗靶点包括过氧化物酶体增殖物激活受体γ -辅助激活剂（pgc -1 α）和sirtuins。这些途径为PD治疗的未来治疗发展提供了希望。2009爱思唯尔有限公司版权所有。
A large body of evidence from postmortem brain tissue and genetic analysis in humans, as well as biochemical and pathological studies in animal models of neurodegeneration suggest that mitochondrial dysfunction is a key pathological mechanism in Parkinson's Disease (PD). Mitochondrial dysfunction leads to oxidative stress, damage to mitochondrial DNA, mitochondrial DNA deletions, altered mitochondrial morphology, alterations in mitochondrial fission and fusion and ultimately neuronal demise. Therapeutic approaches targeting mitochondrial dysfunction and oxidative damage, therefore, hold great promise in PD. A number of agents, which target energy metabolism, are presently in therapeutic trials in PD. Both creatine and Coenzyme Q10 (CoQ10) are being tested in phase III clinical trials. In addition, preclinical studies in animal models have shown efficacy of mitochondrial-targeted antioxidants and the SS peptides. A promising approach for increasing antioxidant defenses is to transcriptionally increase the activity of the Nrf2/ARE pathway, which activates transcription of anti-inflammatory and antioxidant genes. A number of agents including sulforaphane, curcumin and triterpenoids have been shown to activate this pathway and to produce neuroprotective effects. Lastly, newly identified therapeutic targets include peroxisomal proliferator activated receptor gamma-coactivator (PGC-1alpha) and sirtuins. These pathways provide promise for future therapeutic developments in the treatment of PD. (C) 2009 Elsevier Ltd. All rights reserved.