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Updated: Aug 23, 2025
Oral Administration of Rotenone using a Gavage and Image Analysis of Alpha-synuclein Inclusions in the Enteric Nervous System
Published on: October 26, 2010
Non-Reproducibility of Oral Rotenone as a Model for Parkinson's Disease in Mice
Ellen Niederberger1,2, Annett Wilken-Schmitz1,2, Christine Manderscheid1
1Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany.
Abstract:
Oral rotenone has been proposed as a model for Parkinson's disease (PD) in mice. To establish the model in our lab and study complex behavior we followed a published treatment regimen. C57BL/6 mice received 30 mg/kg body weight of rotenone once daily via oral administration for 4 and 8 weeks. Motor functions were assessed by RotaRod running. Immunofluorescence studies were used to analyze the morphology of dopaminergic neurons, the expression of alpha-Synuclein (α-Syn), and inflammatory gliosis or infiltration in the substantia nigra. Rotenone-treated mice did not gain body weight during treatment compared with about 4 g in vehicle-treated mice, which was however the only robust manifestation of drug treatment and suggested local gut damage. Rotenone-treated mice had no deficits in motor behavior, no loss or sign of degeneration of dopaminergic neurons, no α-Syn accumulation, and only mild microgliosis, the latter likely an indirect remote effect of rotenone-evoked gut dysbiosis. Searching for explanations for the model failure, we analyzed rotenone plasma concentrations via LC-MS/MS 2 h after administration of the last dose to assess bioavailability. Rotenone was not detectable in plasma at a lower limit of quantification of 2 ng/mL (5 nM), showing that oral rotenone had insufficient bioavailability to achieve sustained systemic drug levels in mice. Hence, oral rotenone caused local gastrointestinal toxicity evident as lack of weight gain but failed to evoke behavioral or biological correlates of PD within 8 weeks.
Insights
Oral rotenone failed to establish a Parkinson's disease (PD) mouse model. Insufficient bioavailability caused gastrointestinal issues but not the expected neurodegeneration or motor deficits. Further research is needed for effective PD models.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- The oral rotenone mouse model is frequently used to study Parkinson's disease (PD).
- This study aimed to replicate and validate this model in a laboratory setting for complex behavioral research.
- Previous research suggests oral rotenone can induce PD-like pathology in rodents.
Purpose of the Study:
- To establish an oral rotenone-induced Parkinson's disease mouse model.
- To assess the efficacy of rotenone in causing neurodegeneration, alpha-Synuclein aggregation, and motor deficits.
- To investigate the bioavailability of orally administered rotenone in mice.
Main Methods:
- C57BL/6 mice were administered 30 mg/kg of rotenone orally daily for 4 or 8 weeks.
- Motor function was evaluated using the RotaRod test.
- Immunofluorescence was employed to examine dopaminergic neuron morphology, alpha-Synuclein expression, and glial activation in the substantia nigra. Plasma rotenone levels were measured using LC-MS/MS.
Main Results:
- Rotenone-treated mice exhibited reduced weight gain, indicating gastrointestinal toxicity, but no motor function deficits.
- No significant loss or degeneration of dopaminergic neurons, alpha-Synuclein accumulation, or substantial neuroinflammation was observed.
- Plasma concentrations of rotenone were undetectable, demonstrating poor oral bioavailability and insufficient systemic exposure.
Conclusions:
- Oral rotenone administration at the tested dosage and duration failed to induce Parkinson's disease-like pathology or behavioral changes in mice.
- The primary effect observed was local gastrointestinal toxicity, likely due to poor systemic absorption.
- The lack of detectable plasma rotenone levels explains the failure to establish a valid Parkinson's disease model using this regimen.
