Intranasal Administration of Rotenone to Mice Induces Dopaminergic Neurite Degeneration of Dopaminergic Neurons in the Substantia Nigra

Abstract

Exposure to environmental neurotoxins is suspected to be a risk factor for sporadic progressive neurodegenerative diseases. Parkinson's disease has been associated with exposure to the pesticide rotenone, a mitochondrial respiration inhibitor. We previously reported that intranasal administration of rotenone in mice induced dopaminergic (DA) neurodegeneration in the olfactory bulb (OB) and reduced olfactory functions. In the present study, we investigated the DA neurons in the brains of mice that were administered rotenone intranasally for an extended period. We found that the olfactory function of mice was attenuated by rotenone administration. Electrophysiological analysis of the mitral cells, which are output neurons in the OB, revealed that the inhibitory input into the mitral cells was retarded. In the immunohistochemical analysis, neurite degeneration of DA neurons in the substantia nigra was observed in rotenone-administered mice, indicating that rotenone progressively initiated the degeneration of cerebral DA neurons via the nasal route.Key words dopaminergic neuron; intranasal administration; olfactory bulb; rotenone; substantia nigra Environmental chemicals are suspected to be risk factors for neurodegenerative diseases.1) One case control study indicated an association between Parkinson's disease (PD) and the use of a group of pesticides that inhibit mitochondrial complex I, which included rotenone and paraquat.2) PD is characterized by degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc).3) DA neurons are vulnerable to reactive oxygen species (ROS) generated by aberrant mitochondrial respiration.4) Subcutaneous chronic infusion or direct brain infusion of rotenone induces DA neurodegeneration in the substantia nigra (SN) and features of PD in rats, suggesting that exposure to neurotoxins such as rotenone is a risk factor for PD. 5,6) In general, exposure of the human brain to environmental chemicals occurs following the intake of such chemicals by ingestion, cutaneous contact, or inhalation. Various chemicals absorbed at the olfactory mucosa reach the brain directly through passive diffusion from the extra-neural space of olfactory nerves to the cerebrospinal fluid and/or by the active axonal transport of olfactory neurons. 7,8) Prediger et al. postulated that some forms of PD may be caused by environmental agents delivered to the brain via the olfactory mucosa. 9)PD patients often suffer dysosmia as their first symptom. 10)In the olfactory bulb (OB), a primary center for olfactory information processing, DA neurons function as inhibitory interneurons increasing the dynamic range of information transfer from olfactory receptor neurons to OB neurons 11) and maintaining the odor discriminating ability.12) Huisman et al. reported that DA neurons in the OB increased in postmortem autopsy of PD patients, suggesting an increase in inhibitory inputs of dopamine into olfactory nerve terminals could reduce olfactory functions.13) We used one-week rotenone administration to th...

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

“…63 Where authors dissolved in DMSO and reduced exposure of rotenone to water and then administered intranasally, qualitative parkinsonian signs were observed already at 14 d (SNpc TH loss, striatal TH loss). 54 When using this latter protocol, the authors also noted consistent olfactory deficits. 54,62 These authors are among the very few that have used female mice, which are more sensitive to rotenone, and we do further note that the intranasal aqueous rotenone protocol used males.…”

“…54 When using this latter protocol, the authors also noted consistent olfactory deficits. 54,62 These authors are among the very few that have used female mice, which are more sensitive to rotenone, and we do further note that the intranasal aqueous rotenone protocol used males.…”

“…Rotenone is stable in the solid state, but importantly, rotenone is known to degrade in water; 5 thus, use of/exposure to water during preparation for administration should be minimal. 54 Furthermore, exposure to light is also undesirable, 55 for example, it has been shown that the concentration of rotenone on a glass surface decreases by 19% in 8 h and by 46% in 24 h under a UV lamp (365 nm, distance 10 cm). 56 Temperature also affects degradation, for example, half-life values in soil ranged from 21 to 25 days at 10 °C and 5−8 days at 20 °C, and in water the role of temperature is even more important as the degradation rate was over 10 times faster in warm than in cold water.…”

“…Olfactory deficits, another early, nonmotor feature of PD, 147 are observed when using inhalation as a route of exposure. 54,62,138,139 The role played by pharmacokinetic differences in the risk of development of PD in humans following chronic exposure to rotenone is unknown. Rotenone-induced animal models of PD suggest that pharmacokinetics is critical and influences model development.…”

High Pesticide Exposure Events and Olfactory Impairment among U.S. Farmers

“…Studies using PD rodent models also suggest that rotenone (Sasajima et al. 2015, 2017) and paraquat (Czerniczyniec et al. 2011; Nuber et al.…”