Lipinski Daniel M, Barnard Alun R, Singh Mandeep S, Martin Chris, Lee Edward J, Davies Wayne I L, MacLaren Robert E
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; Department of Ophthalmology, University of Florida, Gainesville, Florida, USA.
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
Mol Ther. 2015 Aug;23(8):1308-1319. doi: 10.1038/mt.2015.68. Epub 2015 Apr 21.
The long-term outcome of neuroprotection as a therapeutic strategy for preventing cell death in neurodegenerative disorders remains unknown, primarily due to slow disease progression and the inherent difficulty of assessing neuronal survival in vivo. Employing a murine model of retinal disease, we demonstrate that ciliary neurotrophic factor (CNTF) confers life-long protection against photoreceptor degeneration. Repetitive retinal imaging allowed the survival of intrinsically fluorescent cone photoreceptors to be quantified in vivo. Imaging of the visual cortex and assessment of visually-evoked behavioral responses demonstrated that surviving cones retain function and signal correctly to the brain. The mechanisms underlying CNTF-mediated neuroprotection were explored through transcriptome analysis, revealing widespread upregulation of proteolysis inhibitors, which may prevent cellular/extracellular matrix degradation and complement activation in neurodegenerative diseases. These findings provide insights into potential novel therapeutic avenues for diseases such as retinitis pigmentosa and amyotrophic lateral sclerosis, for which CNTF has been evaluated unsuccessfully in clinical trials.
作为预防神经退行性疾病中细胞死亡的一种治疗策略，神经保护的长期效果仍然未知，这主要是由于疾病进展缓慢以及在体内评估神经元存活存在固有的困难。利用一种视网膜疾病的小鼠模型，我们证明睫状神经营养因子（CNTF）能提供终身保护，防止光感受器退化。重复性视网膜成像使体内固有荧光视锥光感受器的存活得以量化。视觉皮层成像和视觉诱发行为反应评估表明，存活的视锥细胞保留功能并能正确地向大脑发送信号。通过转录组分析探索了CNTF介导的神经保护的潜在机制，结果显示蛋白水解抑制剂广泛上调，这可能会阻止神经退行性疾病中的细胞/细胞外基质降解和补体激活。这些发现为诸如色素性视网膜炎和肌萎缩侧索硬化症等疾病的潜在新治疗途径提供了见解，在这些疾病的临床试验中，CNTF的评估未获成功。
