The deficit of dopaminergic neurons in the nigrostriatal pathway is one of the pathological features of Parkinson’s disease (PD). The decline of vesicular monoamine transporter type 2 (VMAT2) has been verified to relate with the severity of PD. The purpose of this study was to evaluate the ability of [F]fluoropropyl-(+)-dihydrotetrabenazine ([F]FP-(+)-DTBZ) to detect dopaminergic neuron dysfunction in a standard rat model of PD using PET imaging. Specifically, two different doses of 6-hydroxydopamine (6-OHDA) were injected unilaterally into the medial forebrain bundle (MFB) to create the models with two different severities.
Male Sprague-Dawley rats were intracranially injected with 8 μg 6-OHDA (partial lesion group), 16 μg 6-OHDA (full lesion group) and vehicle (sham group) into MFB, respectively. Thirty minutes static [F]FP-(+)-DTBZ microPET scanning was performed to determine the dopaminergic neuron integrity on the 28th day post-injection and the behavioral tests were carried out in the next two days. Then, the rats were decapitated, and the brains were collected for biogenic amines content analysis or dissected for autoradiography and immunohistochemical (IHC) staining. The correlations of PET results to the behavioral, biological, histological, autoradiography results were analyzed, respectively.
The standardized uptake value ratio (ST to CB) of [F]FP-(+)-DTBZ in the ipsilateral striata decreased significantly in partial lesion group and full lesion group. Compared with the sham group, the ratio of the standardized uptake value in ipsilateral striatum to that in contralateral striatum decreased by 57.09 ± 2.30% (full lesion group) and 25.31 ± 5.70% (partial lesion group), respectively. The dopaminergic neuronal dysfunction was corroborated by in vitro autoradiography, IHC, and quantitative analysis of DA as well as its metabolites concentration tests. The motor function impairments of 6-OHDA-treated animals were manifested by a series of behavioral tests. The results of microPET imaging were linearly correlated with behavioral, biological, histological, and autoradiography results, respectively.
Our data suggest that [F]FP-(+)-DTBZ may be useful for detecting different degrees of dopaminergic neuronal lesions by PET imaging in PD models induced by 6-OHDA.
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