To clarify the mechanism of neurodegeneration in PD and to develop disease-modifying drugs for PD treatment, animal models which reproduce the pathological hallmarks and clinical features of PD are required. Because PD neuropathology is not restricted to the nigrostriatal DA pathway, reproducibility of central and peripheral features of PD in animal models has been focused upon. Rotenone models of PD have received most attention because the pesticide can reproduce pathological conditions of PD. To date, various studies demonstrated that rotenone treatment by different routes of administration induced central and peripheral neuropathological features and motor and non-motor PD-like symptoms as a consequence of neuropathological changes (Figure 1
and Table 1
). Rotenone can induce degeneration of nigrostriatal DA pathway with Lewy pathology and motor dysfunction, which responds to DA agonists. In addition, rotenone also causes time-dependent neuropathological changes in the CNS, such as in the olfactory bulb, hippocampus, locus coeruleus, and pedunculopontine tegmental nucleus, that correspond to Braak’s staging hypothesis. Moreover, rotenone can initiate PD-like pathology and α-synuclein accumulation in the ENS, subsequently inducing propagation of α-synuclein to the DMV, possibly by the transneuronal and retrograde axonal transport. Accordingly, these extensive neurotoxic effects of rotenone can recapitulate non-motor symptoms, such as olfactory, gastrointestinal, and cardiovascular dysfunction, depression, sleep disorders, cognitive impairment, and hyperalgesia, which precede motor deficits, similar to those observed in prodromal PD (Figure 1
). The utility of rotenone models in the development of disease-modifying drugs is substantiated in the previous reports. Perez-Pardo et al. demonstrated that uridine and fish oil diet prevented rotenone-induced gastrointestinal pathology and dysfunction in both oral and intrastriatal rotenone exposure in mice [44
]. Farombi et al. also reported that kolaviron, a natural anti-inflammatory, anti-oxidative, and anti-apoptotic biflavonoid, ameliorated oxidative stress in the gut and intestinal barrier deficits in stereotaxic rotenone models [78
]. Recently, we reported that intake of coffee components, caffeic acid and chlorogenic acid, enhanced the antioxidative properties of enteric glial cells and prevented rotenone-induced neurodegeneration in myenteric plexus [20
]. These results indicate that enteric environmental modification exerts protective effects in the ENS. In addition, based on a hypothesis that PD pathology propagates from the ENS to the CNS, these findings suggest a possible food-based therapeutic strategy for early treatment of PD. Moreover, several studies demonstrated that some drugs and flavonoids improved depression-like behavior [61
] and cognitive and memory impairment [72
] in rotenone models: for example, antidepressive effects of curcumin, melatonin, and ibuprofen, improvement of cognitive and memory impairment by pistachio and carotenoid compound lycopene. Taken together, rotenone models could be useful for the evaluation of candidate drugs for prodromal PD treatment.
Despite these advantages of rotenone models, the adoption of the models, in particular rotenone infusion models, is limiting because of variability in animal sensitivity and the inability of other investigators to consistently reproduce the PD neuropathology. To dissolve this issue, other various routes of administration of rotenone have been developed: intraperitoneal, oral, intragastric, subcutaneous injection, and intranasal inoculation. Especially, oral, intragastric, subcutaneous, and intranasal administrations are unique routes which are based on a background that pesticide exposure, particularly exposure to rotenone and paraquat, increases the risk of PD [14
]. However, these administrations still have disadvantages: high mortality of animals, difficulty in method, and health hazard of investigators exposed to the toxin by daily administration. The variability and reproducibility of rotenone PD models would depend on various routes of administrations and applied animal species. In addition, high mortality of animals exposed to rotenone may lead to unstable experimental results. Recently, we established a high-reproducible rotenone model using C57BL/6J mice [19
]; the rotenone mouse model was produced by chronic systemic exposure to a low dose of rotenone (2.5 mg/kg/day) for 4 weeks by subcutaneous implantation of rotenone-filled mini pump. Our rotenone models exhibited motor deficits and gastrointestinal dysfunction as a consequence of neurodegeneration with α-synuclein accumulation in the SNpc, DMV, and the intestinal myenteric plexus. The survival rate of rotenone-treated mice was not different from that of control group. The zero mortality is extremely important because that leads to stability of rotenone sensitivity. Furthermore, simple administration of pump implantation enables other investigators to reproduce rotenone toxicity constantly. To date, most of the rotenone models were produced in rats [80
]. Although the pathogenesis in sporadic PD remains unknown, there is a consensus that both genetic and environmental factors are thought to contribute to PD pathogenesis. Thus, the rotenone model using C57BL mice, which is a common strain of genetically modified animal, could be expanded to genetic mouse models of PD, and that could provide useful animal models to investigate possible interaction between pesticide exposure and genetic defects. Our low-dose rotenone mouse model would contribute to investigation of PD pathogenesis and development of disease-modifying drugs for PD in the future.