Rojas Julio C, Gonzalez-Lima Francisco
Departments of Psychology, Pharmacology and Toxicology, University of Texas at Austin, Austin, TX, USA.
Eye Brain. 2010 Mar 10;2:21-37. doi: 10.2147/eb.s9363. eCollection 2010.
This review summarizes the characteristics of a rodent toxicologic model of optic neuropathy induced by the mitochondrial complex I inhibitor rotenone. This model has been developed to fulfill the demand for a drug-screening tool providing a sound mechanistic context to address the role of mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders. It features biochemical, structural, and functional retinal deficits that resemble those of patients with Leber's hereditary optic neuropathy, a mitochondrial disease characterized by selective degeneration of retinal ganglion cells, and for which an environmental component is believed to play a major triggering role. The available data support the efficiency, sensitivity, and versatility of the model for providing insights into the mechanisms of neurodegeneration, including mitochondrial dysfunction, oxidative stress and excitotoxicity. Screening work with this model has provided proof-of-principle that interventions targeting the electron transport chain, such as USP methylene blue and near-infrared light therapy, are effective at preventing neurodegeneration induced by mitochondrial dysfunction . Prospective developments of this model include the use of neuronal reporter genes for non-invasive assessment of retinal degeneration at different time points, and its combination with genetic approaches to elucidate the synergism of environmental and genetic factors in neurodegeneration.
本综述总结了由线粒体复合物I抑制剂鱼藤酮诱导的啮齿动物视神经病变毒理学模型的特征。开发该模型是为了满足对药物筛选工具的需求，该工具能为解决线粒体功能障碍在神经退行性疾病发病机制中的作用提供合理的机制背景。它具有生化、结构和功能性视网膜缺陷，类似于患有Leber遗传性视神经病变的患者，这是一种以视网膜神经节细胞选择性变性为特征的线粒体疾病，据信环境因素在其中起主要触发作用。现有数据支持该模型在深入了解神经退行性变机制（包括线粒体功能障碍、氧化应激和兴奋性毒性）方面的有效性、敏感性和通用性。使用该模型进行的筛选工作已提供原理证明，即针对电子传递链的干预措施，如美国药典亚甲蓝和近红外光疗法，可有效预防线粒体功能障碍诱导的神经退行性变。该模型的未来发展包括使用神经元报告基因在不同时间点对视网膜变性进行非侵入性评估，以及将其与基因方法相结合，以阐明环境和遗传因素在神经退行性变中的协同作用。
