Department of Neurology, RWTH Aachen University, Aachen, Germany.
JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany.
J Neurochem. 2018 Dec;147(5):678-691. doi: 10.1111/jnc.14575. Epub 2018 Nov 13.
Parkinson's disease (PD) is characterized by the loss of midbrain dopaminergic neurons and aggregates of α-synuclein termed Lewy bodies. Fingolimod (FTY720) is an agonist of sphingosine-1 phosphate receptors and an approved oral treatment for multiple sclerosis. Fingolimod elevates brain-derived neurotrophic factor (BDNF), an important neurotrophic factor for dopaminergic neurons. BDNF and fingolimod are beneficial in several animal models of PD. In order to validate the therapeutic potential of fingolimod for the treatment of PD, we tested its effect in the subacute MPTP mouse model of PD. MPTP or vehicle was applied i.p. in doses of 30 mg/kg MPTP on five consecutive days. In order to recapitulate the combination of dopamine loss and α-synuclein aggregates found in PD, MPTP was first administered in Thy1-A30P-α-synuclein transgenic mice. Fingolimod was administered i.p. at a dose of 0.1 mg/kg every second day. Nigrostriatal degeneration was assayed by stereologically counting the number of dopaminergic neurons in the substantia nigra pars compacta, by analysing the concentration of catecholamines and the density of dopaminergic fibres in the striatum. MPTP administration produced a robust nigrostriatal degeneration, comparable to previous studies. Unexpectedly, we found no difference between mice with and without fingolimod treatment, neither at baseline, nor at 14 or 90 days after MPTP. Also, we found no effect of fingolimod in the subacute MPTP mouse model when we used wildtype mice instead of α-synuclein transgenic mice, and no effect with an increased dose of 1 mg/kg fingolimod administered every day. In order to explain these findings, we analysed BDNF regulation by fingolimod. We did find an increase of BDNF protein after a single injection of fingolimod 0.1 or 1.0 mg/kg, but not after multiple injections, indicating that the BDNF response to fingolimod is unsustainable over time. Taken together we did not observe a neuroprotective effect of fingolimod in the subacute MPTP mouse model of PD. We discuss possible explanations for this discrepancy with previous findings and conclude fingolimod might be beneficial for the nonmotor symptoms of PD. OPEN SCIENCE BADGES: This article has received a badge for Open Materials and Open Data because it provided all relevant information to reproduce the study in the manuscript and because it made the data publicly available. The data can be accessed at https://osf.io/6xgfn/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
帕金森病（PD）的特征是中脑多巴胺能神经元丧失和称为路易体的α-突触核蛋白聚集。芬戈莫德（FTY720）是一种鞘氨醇-1-磷酸受体激动剂，已被批准用于治疗多发性硬化症。芬戈莫德可提高脑源性神经营养因子（BDNF），这是一种对多巴胺能神经元很重要的神经营养因子。BDNF 和芬戈莫德对几种 PD 动物模型均有益。为了验证芬戈莫德治疗 PD 的治疗潜力，我们在亚急性 MPTP 小鼠 PD 模型中测试了其效果。MPTP 或载体以 30mg/kg MPTP 的剂量腹腔内给药，连续 5 天。为了重现 PD 中发现的多巴胺丧失和α-突触核蛋白聚集的组合，首先在 Thy1-A30P-α-突触核蛋白转基因小鼠中给予 MPTP。芬戈莫德以 0.1mg/kg 的剂量每两天腹腔内给药一次。通过立体学计数黑质致密部多巴胺能神经元的数量、分析纹状体中儿茶酚胺的浓度和多巴胺能纤维的密度来检测黑质纹状体变性。MPTP 给药产生了强大的黑质纹状体变性，与之前的研究相当。出乎意料的是，我们发现在没有和有芬戈莫德治疗的小鼠之间没有差异，无论是在基线时，还是在 MPTP 后 14 或 90 天时。此外，当我们使用野生型小鼠而不是α-突触核蛋白转基因小鼠时，我们在亚急性 MPTP 小鼠模型中没有发现芬戈莫德的作用，并且每天给予 1mg/kg 的增加剂量的芬戈莫德也没有作用。为了解释这些发现，我们分析了芬戈莫德对 BDNF 的调节。我们确实发现单次注射 0.1 或 1.0mg/kg 芬戈莫德后 BDNF 蛋白增加，但多次注射后没有增加，这表明 BDNF 对芬戈莫德的反应是不可持续的。总的来说，我们没有观察到芬戈莫德在亚急性 MPTP 小鼠 PD 模型中的神经保护作用。我们讨论了与之前发现的这种差异的可能解释，并得出结论，芬戈莫德可能对 PD 的非运动症状有益。开放科学徽章：本文因提供了重现研究的所有相关信息，并使数据公开，因此获得了“开放材料”和“开放数据”徽章。可以在 https://osf.io/6xgfn/ 访问数据。本文完整的开放科学披露表格可以在文章末尾找到。有关开放实践徽章的更多信息可以在 https://cos.io/our-services/open-science-badges/ 找到。
