Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone
Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone
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DOI：
10.1016/j.expneurol.2004.01.023
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发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
Chesselet, MF
中科院分区：
文献类型：
--
作者：
Fleming, SM;Zhu, CN;Chesselet, MF
线粒体毒素（例如复合物 1 抑制剂鱼藤酮）广泛用作杀虫剂，并且可能存在于军事环境中。施用鱼藤酮可引起与大鼠帕金森病相似的生化和组织学改变。然而，只有一小部分动物表现出这些作用，并且尚不清楚在那些似乎对其多巴胺能神经末梢的毒性作用具有抵抗力的动物中，长期施用鱼藤酮是否会引起更细微的改变。为了解决这个问题，对成年大鼠静脉内或皮下注射媒介物或鱼藤酮（2.0、2.5或3.5毫克/千克/天）21天，并检查鱼藤酮对生存、运动行为和纹状体酪氨酸羟化酶免疫反应性（TH-IR）的影响。静脉注射和皮下注射鱼藤酮均可导致存活率呈剂量依赖性下降。幸存的动物表现出自发饲养能力下降。一些实验组的运动活动和运动起始时间也发生了变化。证实了之前的结果，在研究早期患病的大鼠和一些服用高剂量鱼藤酮的幸存大鼠中，纹状体中的 TH-IR 显着降低。然而，接受 2.0 mg/kg/天剂量的存活大鼠中，没有一只表现出让人联想到帕金森病的 TH-IR 丧失，并且各剂量纹状体 TH-IR 的丧失与个体大鼠的运动行为不相关。因此，即使在没有出现帕金森氏病组织学症状的动物中，长期服用低剂量的鱼藤酮也会诱发运动异常，这表明体内中度线粒体功能障碍的普遍神经学影响。 (C) 2004 Elsevier Inc. 保留所有权利。
Mitochondrial toxins such as the complex 1 inhibitor rotenone are widely used as pesticides and may be present in military environments. Administration of rotenone can induce biochemical and histological alterations similar to those of Parkinson's disease in rats. However, only a subset of animals show these effects and it is unclear whether more subtle alterations are caused by chronic administration of rotenone in those animals that appear resistant to its toxic effects on dopaminergic nerve terminals. To address this question, vehicle or rotenone (2.0, 2.5, or 3.5 mg/kg/day) was administered intravenously or subcutaneously for 21 days to adult rats, and rotenone effects on survival, motor behavior, and striatal tyrosine hydroxylase immunoreactivity (TH-IR) were examined. Both intravenous and subcutaneous rotenone induced a dose-dependent decrease in survival rates. Surviving animals showed a decrease in spontaneous rearing. Locomotor activity and movement initiation time were also altered in some of the experimental groups. Confirming previous results, TH-IR in the striatum was markedly decreased in rats that fell ill early in the study and in a few of the surviving rats with high rotenone doses. However, none of the surviving rats receiving 2.0 mg/kg/day showed TH-IR loss reminiscent of Parkinson's disease, and loss of striatal TH-IR across doses was not correlated with motor behavior in individual rats. Thus, chronic administration of low doses of rotenone induces motor anomalies even in animals that do not develop histological signs of Parkinson's disease, indicating a pervasive neurological effect of moderate mitochondrial dysfunction in vivo. (C) 2004 Elsevier Inc. All rights reserved.