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

Abstract

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.

Microglial Activation Damages Dopaminergic Neurons through MMP-2/-9-Mediated Increase of Blood-Brain Barrier Permeability in a Parkinson’s Disease Mouse Model

“…Human studies revealed that chronic exposure to rotenone pesticide significantly elevated the risk of PD [ 2 ]. Experimental rodents intoxicated with rotenone also recapitulated the typical features of PD, such as degeneration of nigral dopaminergic neurons, aggregation of α-synuclein, the main component of Lewy bodies, and motor deficits [ 3 ]. Although the exact mechanism of PD remains unclear, strong evidence revealed a critical role of chronic neuroinflammation mediated by brain innate immune microglia cells in dopaminergic neurodegeneration [ 4 , 5 ].…”

Inhibition of 2-Oxoglutarate Dehydrogenase as a Chemical Model of Acute Hypobaric Hypoxia

“…Molecular mechanisms of complex pathophysiological phenomena are often studied in their chemical models. For instance, pentylenetetrazol is widely employed to model epilepsy (1), while mitochondrial impairment in neurodegenerative diseases is often modeled by exposure of animals to inhibitors of the respiratory chain (2,3). The high sensitivity of mitochondrial complex II to inhibition by malonate and 3-nitropropionic acid (3-NP) is used to model Huntington's disease (2,4).…”

“…However, interpretations of similar models employing another such inhibitor, rotenone, are complicated by its side effects, not considered in the original model suggestion. As revealed by now, some of the rotenone actions may be caused not only by targeting complex I of the respiratory chain (3,7). Thus, translational value of the results obtained in the chemical models of pathologies essentially depends on the knowledge of molecular features of the complex pathophysiology, which are reproduced by the model, and those which characterize the substance-specific action.…”

A Critical Review of Zebrafish Models of Parkinson’s Disease

“…It readily crosses the blood brain barrier and is a high-affinity inhibitor of Complex I of the mitochondrial ETC ( Sherer et al, 2003 ; Bové et al, 2005 ). Humans exposed to high levels of rotenone are 2.5 times more likely to develop Parkinsonian-like symptoms than the general population ( Innos and Hickey, 2021 ). In rats, rotenone exposure causes degradation of the nigrostriatal dopaminergic neurons and behavioural symptoms characteristic of PD ( Sherer et al, 2003 ).…”