Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson's disease.
Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson's disease.
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DOI：
10.1186/1471-2202-10-109
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发表时间：
2009-09-01
期刊：
影响因子：
2.4
通讯作者：
Lu B
中科院分区：
文献类型：
--
作者：
Faust K;Gehrke S;Yang Y;Yang L;Beal MF;Lu B
帕金森病（PD）是最常见的运动障碍。锥体外系运动症状源于患者脑内多巴胺能通路的退化。目前PD的治疗是对症治疗，减轻疾病症状而不逆转或延缓疾病进展。虽然PD的病因尚不清楚，但已经确定了几种导致黑质多巴胺能神经元（DN）死亡的致病因素。这些包括氧化应激、线粒体功能障碍、炎症和兴奋性毒性。操纵这些因素可能允许疾病修饰治疗策略的发展，以减缓神经元死亡。果蝇DJ-1A是家族PD基因DJ-1的同系物，抑制果蝇DJ-1A会导致氧化应激、线粒体功能障碍和DN丢失，这使得果蝇DJ-1A模型成为一个很好的体内系统，用于测试具有治疗潜力的化合物。在本研究中，我们使用果蝇DJ-1A模型来测试潜在的神经保护药物。应用的药物有中药celastrol、抗生素米诺环素、生物能胺辅酶Q10 （coQ10）和谷氨酸拮抗剂2,3-二羟基-6-硝基-7-磺胺基苯并[f]-喹啉（NBQX）。所有这些药物都针对PD中涉及的致病过程，因此构成了基于机制的治疗策略。我们发现，celastrol和米诺环素都具有抗氧化和抗炎特性，在果蝇DJ-1A模型中赋予有效的多巴胺能神经保护作用，而coQ10则没有保护作用。NBQX对细胞存活和脑多巴胺含量有不同的影响：它可以防止DN丢失，但不能恢复脑多巴胺水平。本研究进一步验证了果蝇作为具有神经退行性疾病治疗潜力的药物临床前测试的有价值模型。低成本和高通量测试使果蝇PD模型成为筛选新型治疗化合物的有效体内工具。如果我们的发现能够在哺乳动物PD模型中得到进一步验证，它们将意味着结合抗氧化和抗炎特性的药物将成为基于机制的PD治疗的强有力的治疗候选者。
Parkinson's disease (PD) is the most common movement disorder. Extrapyramidal motor symptoms stem from the degeneration of the dopaminergic pathways in patient brain. Current treatments for PD are symptomatic, alleviating disease symptoms without reversing or retarding disease progression. Although the cause of PD remains unknown, several pathogenic factors have been identified, which cause dopaminergic neuron (DN) death in the substantia nigra (SN). These include oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity. Manipulation of these factors may allow the development of disease-modifying treatment strategies to slow neuronal death. Inhibition of DJ-1A, the Drosophila homologue of the familial PD gene DJ-1, leads to oxidative stress, mitochondrial dysfunction, and DN loss, making fly DJ-1A model an excellent in vivo system to test for compounds with therapeutic potential. In the present study, a Drosophila DJ-1A model of PD was used to test potential neuroprotective drugs. The drugs applied are the Chinese herb celastrol, the antibiotic minocycline, the bioenergetic amine coenzyme Q10 (coQ10), and the glutamate antagonist 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo[f]-quinoxaline (NBQX). All of these drugs target pathogenic processes implicated in PD, thus constitute mechanism-based treatment strategies. We show that celastrol and minocycline, both having antioxidant and anti-inflammatory properties, confer potent dopaminergic neuroprotection in Drosophila DJ-1A model, while coQ10 shows no protective effect. NBQX exerts differential effects on cell survival and brain dopamine content: it protects against DN loss but fails to restore brain dopamine level. The present study further validates Drosophila as a valuable model for preclinical testing of drugs with therapeutic potential for neurodegenerative diseases. The lower cost and amenability to high throughput testing make Drosophila PD models effective in vivo tools for screening novel therapeutic compounds. If our findings can be further validated in mammalian PD models, they would implicate drugs combining antioxidant and anti-inflammatory properties as strong therapeutic candidates for mechanism-based PD treatment.