Subacute systemic 3-nitropropionic acid intoxication induces a distinct motor disorder in adult C57B1/6 mice: Behavioural and histopathological characterisation
Subacute systemic 3-nitropropionic acid intoxication induces a distinct motor disorder in adult C57B1/6 mice: Behavioural and histopathological characterisation
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DOI：
10.1016/s0306-4522(02)00205-1
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发表时间：
2002-01-01
期刊：
影响因子：
3.3
通讯作者：
Tison, F
中科院分区：
文献类型：
--
作者：
Fernagut, PO;Diguet, E;Tison, F
关于全身性3-硝基丙酸（一种线粒体琥珀酸脱氢酶的不可逆抑制剂）诱导的小鼠运动行为障碍及其组织病理学相关性的数据很少。因此，我们使用标准行为测试、组织病理学相关性和体内磁共振成像进一步表征了亚急性3-硝基丙酸诱导的C57 Bl/6小鼠运动障碍及其时程。首先，我们研究了两个中毒范例（340和560毫克3-硝基丙酸/公斤，7天）相比，控制。低剂量方案仅诱导轻微的运动变化（后肢步长和直立减少）。高剂量方案诱导显著（P <0.05）行为和感觉运动整合缺陷（杆测试、旋转棒、步长、旷场自发活动），但在第1周时致死率为37.5%。临床运动障碍包括后肢紧握和肌张力障碍、躯干肌张力障碍、运动迟缓和姿势控制受损。组织学检查发现，62.5%的小鼠背外侧纹状体出现离散性病变，纹状体体积缩小32%（P <0.0001），外侧纹状体钙结合蛋白-D28 K免疫反应性降低，纹状体输出通路中甲硫氨酸脑啡肽和P物质表达减少。黑质腹侧部多巴胺能神经元丢失30-40%，差异有统计学意义（P <0.05）。其次，我们验证了一个半定量的行为量表来描述运动缺陷的时间过程，并预测纹状体损伤的发生。我们试图确定它是否也可以通过磁共振成像在体内显示。该量表与纹状体体积减少相关（r（2）= 0. 57)和纹状体细胞丢失（r（2）= 0.87），但不伴有纹状体多巴胺能末梢的丢失（多巴胺转运体结合）。纹状体病变内T2信号强度的增加与细胞损失相关（r（2）= 0.66）。我们得出结论，在C57 Bl/6小鼠中全身给予3-硝基丙酸诱导了明显的运动障碍和剂量依赖性纹状体黑质损伤，这可能用于模拟人类基底神经节疾病。(C)2002年IBRO。由爱思唯尔科技有限公司出版。保留所有权利。
Data on motor behavioural disorders induced by systemic 3-nitropropionic acid, an irreversible inhibitor of mitochondrial succinate dehydrogenase and their histopathological correlates in mice, are sparse. We thus further characterised the subacute 3-nitropropionic-acid-induced motor disorder and its time course in C57Bl/6 mice using standard behavioural tests, histopathological correlates and in vivo magnetic resonance imaging. Firstly, we studied two intoxication paradigms (340 and 560 mg 3-nitropropionic acid/kg, 7 days) compared to controls. The low-dose regimen induced only slight motor changes (reduced hindlimb stride length and rearing). The high-dose regimen induced significant (P < 0.05) behavioural and sensorimotor integration deficits (pole test, rotarod, stride length, open-field spontaneous activity) but with 37.5% lethality at week one. The clinical motor disorder consisted of hindlimb clasping and dystonia, truncal dystonia, bradykinesia and impaired postural control. Histopathologically, there were discrete lesions of the dorsolateral striatum in 62.5% of mice together with a 32% reduction (P < 0.0001) of the striatal volume, reduced caldbindin-D28K immunoreactivity in the lateral striatum, and met-enkephalin and substance P in the striatal output pathways. There was also a significant (P < 0.05) 30-40% dopaminergic cell loss within the substantia nigra pars compacta. Secondly, we validated a semi-quantitative behavioural scale to describe the time course of the motor deficits and to predict the occurrence of striatal damage. We sought to determine whether it could also be disclosed in vivo by magnetic resonance imaging. The scale correlated with the striatal volume reduction (r(2) = 0. 57) and striatal cell loss (r(2) = 0.87) but not with the loss of striatal dopaminergic terminals (dopamine transporter binding). Increased T2-signal intensity within the striatal lesion correlated with the cell loss (r(2) = 0.66).We conclude that systemic administration of 3-nitropropionic acid in C57Bl/6 mice induces a distinct motor disorder and dose-dependent striatonigral damage, which are potentially useful to model human diseases of the basal ganglia. (C) 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved.