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

Abstract

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 [18 F]fluoropropyl-carbomethoxyiodo-phenyltropane (FP-CIT) animal positron emission tomography (PET) imaging. The 6-OHDA model (n=10) was induced by unilateral injec-tion 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 out-comes 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.