Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus of Gualtar, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Mol Neurobiol. 2019 May;56(5):3626-3637. doi: 10.1007/s12035-018-1332-1. Epub 2018 Sep 1.
Spinocerebellar ataxias are dominantly inherited neurodegenerative disorders with no disease-modifying treatment. We previously identified the selective serotonin reuptake inhibitor citalopram as a safe and effective drug to be repurposed for Machado-Joseph disease. Pre-symptomatic treatment of transgenic (CMVMJD135) mice strikingly ameliorated mutant ataxin-3 (ATXN3) pathogenesis. Here, we asked whether citalopram treatment initiated at a post-symptomatic age would still show efficacy. We used a cohort of CMVMJD135 mice that shows increased phenotypic severity and faster disease progression (CMVMJD135hi) compared to the mice used in the first trial. Groups of hemizygous CMVMJD135hi mice were orally treated with citalopram. Behavior, protein analysis, and pathology assessment were performed blindly to treatment. Our results show that even when initiated after symptom onset, treatment of CMVMJD135hi mice with citalopram ameliorated motor coordination and balance, attenuating disease progression, albeit to a lesser extent than that seen with pre-symptomatic treatment initiation. There was no impact on ATXN3 aggregation, which contrasts with the robust reduction in ATXN3-positive inclusions observed in CMVMJD135 mice, when treated pre-symptomatically. Post-symptomatic treatment of CMVMJD135hi mice revealed, however, a limited neuroprotective effect by showing a tendency to repair cerebellar calbindin staining, and to increase the number of motor neurons and of NeuN-positive cells in certain brain regions. While supporting that early initiation of treatment with citalopram leads to a marked increase in efficacy, these results strengthen our previous observation that modulation of serotonergic signaling by citalopram is a promising therapeutic approach for Machado-Joseph disease even after symptom onset.
脊髓小脑共济失调是一种显性遗传性神经退行性疾病，目前尚无治疗方法。我们之前发现选择性 5-羟色胺再摄取抑制剂西酞普兰是一种安全有效的药物，可以重新用于治疗 Machado-Joseph 病。在转基因（CMVMJD135）小鼠出现症状前进行治疗，可显著改善突变型 ATXN3（ATXN3）发病机制。在此，我们想知道在出现症状后开始西酞普兰治疗是否仍有效。我们使用了一组 CMVMJD135 小鼠，与第一次试验中使用的小鼠相比，该组小鼠的表型严重程度增加，疾病进展更快（CMVMJD135hi）。一组 CMVMJD135hi 杂合子小鼠进行了西酞普兰口服治疗。对行为、蛋白质分析和病理评估进行了盲法处理。结果表明，即使在出现症状后开始治疗，CMVMJD135hi 小鼠的西酞普兰治疗也可改善运动协调和平衡，减缓疾病进展，尽管其效果不如出现症状前治疗时明显。对 ATXN3 聚集没有影响，这与我们之前观察到的在 CMVMJD135 小鼠中，西酞普兰治疗前显著减少 ATXN3 阳性包涵体形成的结果形成对比。然而，CMVMJD135hi 小鼠的症状后治疗显示出有限的神经保护作用，表现为小脑钙结合蛋白染色修复的趋势，并增加了某些脑区的运动神经元和 NeuN 阳性细胞的数量。虽然支持西酞普兰治疗的早期启动可显著提高疗效，但这些结果强化了我们之前的观察结果，即西酞普兰对 5-羟色胺能信号的调节是 Machado-Joseph 病的一种有前途的治疗方法，即使在出现症状后也是如此。
