Preclinical Evidence Supporting Early Initiation of Citalopram Treatment in Machado-Joseph Disease
Preclinical Evidence Supporting Early Initiation of Citalopram Treatment in Machado-Joseph Disease
复制标题
DOI：
10.1007/s12035-018-1332-1
复制
发表时间：
2019-05-01
影响因子：
5.1
通讯作者：
Maciel, Patricia
中科院分区：
文献类型：
--
作者：
Esteves, Sofia;Oliveira, Stephanie;Maciel, Patricia
脊髓小脑共济失调主要是遗传性神经退行性疾病，没有疾病改善治疗。我们之前确定选择性血清素再摄取抑制剂西酞普兰是一种安全有效的药物，可用于治疗Machado-Joseph病。转基因（CMVMJD135）小鼠的症状前治疗显著改善了突变ataxin-3 （ATXN3）的发病机制。在这里，我们询问在症状后年龄开始的西酞普兰治疗是否仍然有效。与第一次试验中使用的小鼠相比，我们使用的CMVMJD135小鼠队列显示出表型严重程度增加和疾病进展更快（CMVMJD135hi）。半合子CMVMJD135hi小鼠组口服西酞普兰。行为学、蛋白分析、病理评估均为盲法治疗。我们的研究结果表明，即使在症状出现后开始，用西酞普兰治疗CMVMJD135hi小鼠也能改善运动协调和平衡，减缓疾病进展，尽管程度低于症状前开始治疗。对ATXN3聚集没有影响，这与在CMVMJD135小鼠中观察到的ATXN3阳性包裹体的显著减少形成对比，当症状前治疗时。然而，对CMVMJD135hi小鼠进行对症治疗后，显示出有限的神经保护作用，显示出修复小脑calbindin染色的倾向，并增加运动神经元和某些脑区neun阳性细胞的数量。虽然支持早期开始使用西酞普兰治疗可显著提高疗效，但这些结果加强了我们之前的观察，即西酞普兰调节血清素能信号是一种有希望的治疗Machado-Joseph病的方法，即使在症状出现后也是如此。
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.