Using Rotenone to Model Parkinson’s Disease in Mice: A Review of the Role of Pharmacokinetics,Chemical Research in Toxicology

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Using Rotenone to Model Parkinson’s Disease in Mice: A Review of the Role of Pharmacokinetics
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-05-07 , DOI: 10.1021/acs.chemrestox.0c00522
Jürgen Innos ₁ , Miriam A Hickey ₁

Affiliation

Rotenone is a naturally occurring toxin that inhibits complex I of the mitochondrial electron transport chain. Several epidemiological studies have shown an increased risk of Parkinson’s disease (PD) in individuals exposed chronically to rotenone, and it has received great attention for its ability to reproduce many critical features of PD in animal models. Laboratory studies of rotenone have repeatedly shown that it induces in vivo substantia nigra dopaminergic cell loss, a hallmark of PD neuropathology. Additionally, rotenone induces in vivo aggregation of α-synuclein, the major component of Lewy bodies and Lewy neurites found in the brain of PD patients and another hallmark of PD neuropathology. Some in vivo rotenone models also reproduce peripheral signs of PD, such as reduced intestinal motility and peripheral α-synuclein aggregation, both of which are thought to precede classical signs of PD in humans, such as cogwheel rigidity, bradykinesia, and resting tremor. Nevertheless, variability has been noted in cohorts of animals exposed to the same rotenone exposure regimen and also between cohorts exposed to similar doses of rotenone. Low doses, administered chronically, may reproduce PD symptoms and neuropathology more faithfully than excessively high doses, but overlap between toxicity and parkinsonian motor phenotypes makes it difficult to separate if behavior is examined in isolation. Rotenone degrades when exposed to light or water, and choice of vehicle may affect outcome. Rotenone is metabolized extensively in vivo, and choice of route of exposure influences greatly the dose used. However, male rodents may be capable of greater metabolism of rotenone, which could therefore reduce their total body exposure when compared with female rodents. The pharmacokinetics of rotenone has been studied extensively, over many decades. Here, we review these pharmacokinetics and models of PD using this important piscicide.

中文翻译：

使用鱼藤酮模拟小鼠帕金森病：药代动力学作用综述

鱼藤酮是一种天然毒素，可抑制线粒体电子传递链的复合物 I。几项流行病学研究表明，长期暴露于鱼藤酮的个体患帕金森病 (PD) 的风险增加，并且因其在动物模型中重现 PD 的许多关键特征的能力而受到极大关注。鱼藤酮的实验室研究一再表明，它在体内诱导黑质多巴胺能细胞丢失，这是 PD 神经病理学的标志。此外，鱼藤酮诱导 α-突触核蛋白的体内聚集，α-突触核蛋白是 PD 患者大脑中路易小体和路易神经突的主要成分，也是 PD 神经病理学的另一个标志。一些体内鱼藤酮模型也重现了 PD 的外周迹象，如肠道运动减少和外周 α-突触核蛋白聚集，这两者都被认为先于人类 PD 的经典症状，例如齿轮僵硬、运动迟缓和静止性震颤。然而，已经注意到暴露于相同鱼藤酮暴露方案的动物队列以及暴露于相似剂量鱼藤酮的队列之间的变异性。长期服用低剂量可能比过高剂量更忠实地再现 PD 症状和神经病理学，但如果单独检查行为，毒性和帕金森运动表型之间的重叠使得难以区分。鱼藤酮暴露在光或水中时会降解，并且载体的选择可能会影响结果。鱼藤酮在体内广泛代谢，接触途径的选择对所用剂量有很大影响。然而，雄性啮齿动物可能能够更好地代谢鱼藤酮，因此，与雌性啮齿动物相比，这可以减少它们的全身暴露。几十年来，鱼藤酮的药代动力学已被广泛研究。在这里，我们使用这种重要的杀鱼剂回顾了这些药代动力学和 PD 模型。

更新日期：2021-05-17

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