Neurochemical Characterization of A53T-Alpha-Synuclein and 6-Hydroxydopamine Rat Models for Parkinson's Disease through Animal PET Imaging Analysis.

OBJECTIVE

In preclinical research of Parkinson's disease, several rodent models, notably the classical 6-hydroxydopamine (6-OHDA) model and the A53T-alpha-synuclein model, have been widely used, yet their distinct neurochemical characteristics in conjunction with behavioral and histopathological changes have been scarcely documented.

METHODS

We examined the two rat models of Parkinson's disease and characterized them using [18F]fluoropropyl-carbomethoxyiodophenyltropane (FP-CIT) animal positron emission tomography (PET) imaging. The 6-OHDA model (n=10) was induced by unilateral injection of 6-OHDA into the middle forebrain bundle, while the A53T-alpha-synuclein model (n=10) was mediated by the adeno-associated viral vectors injected into the substantia nigra. We hypothesized that these models would present differential neurochemical profiles, which could reflect their behavioral and histopathological features and potentially serve as a supplementary tool for evaluating the outcomes of interventions in animal experiments.

RESULTS

The striatum showed decreased PET uptake on the affected side compared to the unaffected control side, which was highly correlated with the stepping behaviors (R=0.854; 95% confidence interval [CI], 0.606 to 0.951). The decrease in striatal PET uptake was more pronounced in the 6-OHDA model than in the A53T-alpha-synuclein model : the 6-OHDA model exhibited a 60% decrease (95% CI, 48% to 65%) in the affected side compared the control side, while the A53T-alpha-synuclein model exhibited a 20% decrease (95% CI, -16% to 47%). Interestingly, PET uptake in the forebrain cortical region, including the motor cortex, was exclusively decreased in the 6-OHDA model (p=1.0×10-4 and p=1.2×10-3, respectively), indicating that 6-OHDA model is affected not only in the nigrostriatal system but also in other cortical regions. Conversely, the A53T-alpha-synuclein model showed no significant alterations in these cortical regions.

CONCLUSION

Although the A53T-alpha-synuclein model demonstrates less definitive behavioral changes compared to the 6-OHDA model, it presents a more confined pathophysiological representation of Parkinson's disease and may be better suited for evaluating certain therapeutic interventions when utilized with adequate neurochemical characterization.