Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
Ann Neurol. 2017 Mar;81(3):407-418. doi: 10.1002/ana.24867. Epub 2017 Feb 17.
Machado-Joseph disease (MJD) is a neurodegenerative spinocerebellar ataxia (SCA) associated with an expanded polyglutamine tract within ataxin-3 for which there is currently no available therapy. We previously showed that caffeine, a nonselective adenosine receptor antagonist, delays the appearance of striatal damage resulting from expression of full-length mutant ataxin-3. Here we investigated the ability of caffeine to alleviate behavioral deficits and cerebellar neuropathology in transgenic mice with a severe ataxia resulting from expression of a truncated fragment of polyglutamine-expanded ataxin-3 in Purkinje cells.
Control and transgenic c57Bl6 mice expressing in the mouse cerebella a truncated form of human ataxin-3 with 69 glutamine repeats were allowed to freely drink water or caffeinated water (1g/L). Treatments began at 7 weeks of age, when motor and ataxic phenotype emerges in MJD mice, and lasted up to 20 weeks. Mice were tested in a panel of locomotor behavioral paradigms, namely rotarod, beam balance and walking, pole, and water maze cued-platform version tests, and then sacrificed for cerebellar histology.
Caffeine consumption attenuated the progressive loss of general and fine-tuned motor function, balance, and grip strength, in parallel with preservation of cerebellar morphology through decreasing the loss of Purkinje neurons and the thinning of the molecular layer in different folia. Caffeine also rescued the putative striatal-dependent executive and cognitive deficiencies in MJD mice.
Our findings provide the first in vivo demonstration that caffeine intake alleviates behavioral disabilities in a severely impaired animal model of SCA. Ann Neurol 2017;81:407-418.
Machado-Joseph 病（MJD）是一种与ataxin-3 内扩增的多聚谷氨酰胺链相关的神经退行性脊髓小脑共济失调（SCA），目前尚无可用的治疗方法。我们之前的研究表明，咖啡因是一种非选择性腺苷受体拮抗剂，可延迟因全长突变型 ataxin-3 表达而导致的纹状体损伤的出现。在此，我们研究了咖啡因在转染了含有聚谷氨酰胺扩展突变的 ataxin-3 的截断片段的小鼠中，是否能减轻因小脑浦肯野细胞中表达这种截断片段而导致的严重共济失调的行为缺陷和小脑神经病理学。
让表达在小鼠小脑中的截断形式的人类 ataxin-3（含有 69 个谷氨酰胺重复）的对照和转基因 c57Bl6 小鼠自由饮用水或含咖啡因的水（1g/L）。治疗从 MJD 小鼠出现运动和共济失调表型的 7 周龄开始，持续 20 周。在一系列运动行为范式中对小鼠进行测试，即转棒、平衡木和行走、棒和水迷宫提示平台测试，然后处死以进行小脑组织学检查。
咖啡因的摄入减轻了一般和精细运动功能、平衡和握力的逐渐丧失，同时通过减少浦肯野神经元的丧失和不同叶的分子层变薄来保护小脑形态。咖啡因还挽救了 MJD 小鼠中假定的纹状体依赖的执行和认知缺陷。
我们的发现提供了首个体内证据，表明咖啡因摄入可减轻 SCA 严重受损动物模型中的行为障碍。神经病学 2017；81：407-418。
