Masini D, Lopes-Aguiar C, Bonito-Oliva A, Papadia D, Andersson R, Fisahn A, Fisone G
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Transl Psychiatry. 2017 Apr 11;7(4):e1088. doi: 10.1038/tp.2017.58.
Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by motor impairment and a wide range of non-motor symptoms, including sleep disorders and cognitive and affective deficits. In this study, we used a mouse model of PD based on 6-hydroxydopamine (6-OHDA) to examine the effect of thioperamide, a histamine H3 receptor antagonist, on circadian activity, recognition memory and anxiety. A partial, bilateral 6-OHDA lesion of the striatum reduces motor activity during the active phase of the 24 h cycle. In addition, the lesion disrupts the endogenous circadian rhythm observed when mice are maintained in constant darkness. Administration of thioperamide to 6-OHDA-lesion mice rescues the normal rest/activity cycle. Moreover, thioperamide counteracts the deficit of novel object recognition produced by 6-OHDA. Our experiments show that this memory impairment is accompanied by disrupted gamma oscillations in the hippocampus, which are also rescued by thioperamide. In contrast, we do not observe any modification of the anxiogenic effect of 6-OHDA in response to administration of thioperamide. Our results indicate that thioperamide may act as a multifunctional drug, able to counteract disruptions of circadian rhythm and cognitive deficits associated with PD.
帕金森病（PD）是一种常见的神经退行性疾病，其特征为运动障碍以及一系列非运动症状，包括睡眠障碍、认知和情感缺陷。在本研究中，我们使用了基于6-羟基多巴胺（6-OHDA）的帕金森病小鼠模型，来研究组胺H3受体拮抗剂硫代哌啶对昼夜活动、识别记忆和焦虑的影响。纹状体部分双侧6-OHDA损伤会降低24小时周期活动期的运动活性。此外，该损伤会破坏小鼠在持续黑暗环境中观察到的内源性昼夜节律。给6-OHDA损伤小鼠施用硫代哌啶可恢复正常的休息/活动周期。此外，硫代哌啶可抵消6-OHDA导致的新物体识别缺陷。我们的实验表明，这种记忆损伤伴随着海马体中γ振荡的破坏，而硫代哌啶也可使其恢复。相比之下，我们未观察到硫代哌啶给药对6-OHDA致焦虑作用有任何改变。我们的结果表明，硫代哌啶可能是一种多功能药物，能够抵消与帕金森病相关的昼夜节律紊乱和认知缺陷。
