Behavioral tests predicting striatal dopamine level in a rat hemi-Parkinson's disease model
Behavioral tests predicting striatal dopamine level in a rat hemi-Parkinson's disease model
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DOI：
10.1016/j.neuint.2018.11.005
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发表时间：
2019-01-01
影响因子：
4.2
通讯作者：
Tanaka, Junya
中科院分区：
文献类型：
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作者：
Miyanishi, Kazuya;Choudhury, Mohammed E.;Tanaka, Junya
帕金森氏病(PD)是一种常见的神经退行性疾病，导致运动迟缓、震颤、肌肉僵硬和姿势不稳定。虽然它的主要病理是黑质中的递进性多巴胺(DA)能神经元丢失，但直到大多数DA能神经元丢失时，运动障碍才被认为是明显的，可能是由于克服纹状体DA水平下降的代偿机制所致。即使在动物帕金森病模型中，当大多数DA能神经元功能正常时，也很难检测到运动障碍。在本研究中，我们使用不同纹状体DA水平的6-羟基多巴胺(OHDA)和脂多糖(LPS)诱导的半帕金森病模型大鼠，进行了不同的行为学测试(阿朴吗啡诱导的旋转、圆柱形、前爪调整步骤(FAS)、横梁行走、转杆和开阔场地)，以寻找预测疾病早期阶段DA水平的最佳方法。与6-OHDA诱导的模型不同，内毒素模型纹状体DA水平的降低不明显。在行为学测试中，评估前肢运动的气缸测试和FAS测试的数据与DA水平的下降相关性最好。它们与体重增加的减少也有很好的相关性。BEAM和阿朴吗啡试验的相关性不如圆柱法和Fas试验显著。开阔场地和旋转杆测试都没有用。编码酪氨酸羟化酶(TH)的mRNA的表达水平与DA水平有很好的相关性。代谢型谷氨酸受体4mRNA的表达与纹状体DA水平相关，可能与代偿机制有关。这些结果表明，帕金森病的运动障碍应该通过临床环境中的前肢运动或手和前臂的运动来评估，而不是身体或大关节的运动。柱状体法和Fas法相结合可能是评估大鼠帕金森病模型的最佳方法，在该模型中有许多DA能神经元存活。
Parkinson's disease (PD) is a frequent neurodegenerative disease causing bradykinesia, tremor, muscle rigidity and postural instability. Although its main pathology is progressive dopaminergic (DArgic) neuron loss in the substantia nigra, motor deficits are thought not to become apparent until most DArgic neurons are lost, probably due to compensatory mechanisms that overcome the decline of DA level in the striatum. Even in animal PD models, it is difficult to detect motor deficits when most DArgic neurons are functional. In this study, we performed various behavioral tests (apomorphine-induced rotation, cylinder, forepaw adjustment steps (FAS), beam walking, rota-rod, and open-field), using 6-hydroxydopamine (OHDA) and lipopolysaccharide (LPS)-induced hemi-PD model rats with various striatal DA levels, to find the best way to predict the DA level from earlier disease stages. Different from the 6-OHDA-induced model, reduction in the striatal DA levels in the LPS-model was less significant. Among the behavioral tests, data from cylinder and FAS tests, which evaluate forelimb movements, best correlated with decline of the DA level. They also correlated well with decreased body weight gain. The beam and apomorphine tests showed less significant correlation than the cylinder and FAS tests. Open-field and rota-rod tests were not useful. Expressional levels of mRNA encoding tyrosine hydroxylase (TH), a marker of DArgic neurons, correlated well with the DA level. Metabotropic glutamate receptor 4 mRNA expression correlated with the striatal DA level and may be related to compensatory mechanisms. These results suggest that motor impairments of PD should be evaluated by forelimb movements, or hands and forearms in clinical settings, rather than movement of the body or large joints. The combination of cylinder and FAS tests may be the best to evaluate the rat PD models, in which many DArgic neurons survive.