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Evaluation of a multiple system atrophy model in rats using multitracer microPET
Hyung Ho Yoon1, Chong Sik Lee, Seok Ho Hong
1Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Korea.
Background:
A double toxin-double lesion strategy is appropriate for mimicking of striatonigral degeneration. Because knowledge of human pathology is limited, animal models must be well characterized prior to testing of therapeutic approaches to treat multiple system atrophy. In double-toxin animal models, however, reduced contralateral rotation after apomorphine injection is restored within a few weeks via an unknown mechanism; the animals thus revert to PD status. We assessed this phenomenon using multitracer microPET and tissue staining.
Methods:
Five adult male Wistar rats received injections of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB), followed 3 weeks later by injections of quinolinic acid (QA) into the ipsilateral striatum. Apomorphine-induced rotation tests were performed 1 week after each injection, and 6 and 10 weeks after QA injection. Rotarod tests were performed weekly after 6-OHDA injection. MSA-p status was characterized by microPET 5 and 10 weeks after QA injection using the tracers 2-deoxy-2-[(18)F]-fluoro-D-glucose ([(18)F]-FDG) and [(18)F]-N-(3-fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl)nortropane ([(18)F]-FP-CIT). Histological changes were evaluated by tyrosine hydroxylase (TH) and cresyl violet staining.
Results:
The numbers of apomorphine-induced rotations increased contralaterally after 6-OHDA lesions were created, but decreased significantly after QA administration (p = 0.007). Five weeks after QA injection, however, contralateral rotation again increased and persisted for 1 month. Rotarod rotation differed significantly between the intact and PD states (p < 0.05), but not between the PD and MSA-p states. MicroPET revealed glucose hypometabolism and dopamine transporter (DAT) impairment on the lesioned side of the striatum 1 and 2 months after QA lesion surgery. Loss of nigral cells was confirmed by TH immunostaining, and striatal atrophy was observed upon cresyl violet staining.
Conclusion:
Pathological changes consistent with MSA-p can be generated by the double toxin-double lesion method and persist during follow-up. Behavioral tests, such as drug-induced rotation and rotarod tests, are not appropriate for long-term follow-up in the MSA-p model, suggesting the need for development of more appropriate behavioral tests.
Insights
This study shows that a double toxin-double lesion model can mimic multiple system atrophy-parkinsonism (MSA-p) pathology. However, standard behavioral tests are unreliable for long-term assessment in this animal model.
Area of Science:
- Neuroscience
- Animal Models
- Neurodegenerative Diseases
Background:
- Striatonigral degeneration, a key feature of multiple system atrophy (MSA), can be modeled using a double toxin-double lesion strategy.
- Accurate characterization of animal models is crucial before testing therapeutic interventions for MSA.
- A known limitation in existing double-toxin models is the transient recovery of motor function, masking the persistent pathology.
Purpose of the Study:
- To assess the long-term pathological and functional changes in a rat model of MSA-parkinsonism (MSA-p) using a double toxin-double lesion approach.
- To evaluate the efficacy of standard behavioral tests for monitoring disease progression in this MSA-p model.
- To investigate the underlying mechanisms of functional recovery observed in this model.
Main Methods:
- Wistar rats underwent 6-hydroxydopamine (6-OHDA) medial forebrain bundle lesions followed by quinolinic acid (QA) striatal injections.
- Apomorphine-induced rotation and rotarod tests were used to assess motor function.
- Positron emission tomography (PET) with [(18)F]-FDG and [(18)F]-FP-CIT, along with tyrosine hydroxylase (TH) and cresyl violet staining, were employed for pathological characterization.
Main Results:
- QA administration significantly reduced contralateral rotation, but this effect reversed within weeks, masking persistent pathology.
- Rotarod tests showed no significant difference between the Parkinson's disease (PD) and MSA-p states.
- MicroPET revealed persistent glucose hypometabolism and dopamine transporter (DAT) deficits, while histology confirmed nigral cell loss and striatal atrophy.
Conclusions:
- The double toxin-double lesion method successfully generates persistent pathological changes consistent with MSA-p.
- Standard behavioral tests, including drug-induced rotation and rotarod tests, are inadequate for long-term evaluation of this MSA-p model.
- Development of more sensitive and specific behavioral tests is necessary for accurate long-term follow-up in MSA-p animal models.
