Chi-Chang Weng1, Siao-Lan Huang2, Zi-An Chen2, Kun-Ju Lin3,4, Ing-Tsung Hsiao2,3,4, Tzu-Chen Yen3, Mei-Ping Kung5, Shiaw-Pyng Wey6,7,8, Ching-Han Hsu9. 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan. 2. Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan. 3. Center for Advanced Molecular Imaging and Translation, Department of Nuclear Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. 4. Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. 5. Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA. 6. Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan. spwey@mail.cgu.edu.tw. 7. Center for Advanced Molecular Imaging and Translation, Department of Nuclear Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. spwey@mail.cgu.edu.tw. 8. Institute of Radiological Research, Chang Gung University and Chang Gung Memorial Hospital, Taoyuan, Taiwan. spwey@mail.cgu.edu.tw. 9. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan. cghsu@mx.nthu.edu.tw.
Abstract
OBJECTIVE: Lactacystin has been used to establish rodent models of Parkinson disease (PD), with cerebral α-synuclein inclusions. This study evaluated the uptake of [18F]9-fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ), a vesicular monoamine transporter type 2 (VMAT2)-targeting radiotracer, through positron emission tomography (PET) in lactacystin-treated rat brains. METHODS: Adult male Sprague-Dawley rats were randomly treated with a single intracranial dose of lactacystin (2 or 5 μg) or saline (served as the sham control) into the left medial forebrain bundle. A 30-min static [18F]FP-(+)-DTBZ brain PET scan was performed following an intravenous [18F]FP-(+)-DTBZ dose (approximately 22 MBq) in each animal at 2 and 3 weeks after lactacystin treatment. Upon completing the last PET scans, the animals were killed, and their brains were dissected for ex vivo autoradiography (ARG) and immunohistochemical (IHC) staining of tyrosine hydroxylase (TH) as well as VMAT2. RESULTS: Both the 2- and 5-μg lactacystin-treated groups exhibited significantly decreased specific [18F]FP-(+)-DTBZ uptake in the ipsilateral striata (I-ST) at 2 weeks (1.51 and 1.16, respectively) and 3 weeks (1.36 and 1.00, respectively) after lactacystin treatment, compared with the uptake in the corresponding contralateral striata (C-ST) (3.48 and 3.08 for the 2- and 5-μg lactacystin-treated groups, respectively, at 2 weeks; 3.36 and 3.11 for the 2- and 5-μg lactacystin-treated groups, respectively, at 3 weeks) and the sham controls (3.34-3.53). Lactacystin-induced decline in I-ST [18F]FP-(+)-DTBZ uptake was also demonstrated through ex vivo ARG, and the corresponding dopaminergic neuron damage was confirmed by the results of TH- and VMAT2-IHC studies. CONCLUSIONS: In this PD model, lactacystin-induced dopaminergic terminal damage in the ipsilateral striatum could be clearly visualized through in vivo [18F]FP-(+)-DTBZ PET imaging. This may serve as a useful approach for evaluating the effectiveness of new treatments for PD.
OBJECTIVE:Lactacystin has been used to establish rodent models of Parkinson disease (PD), with cerebral α-synuclein inclusions. This study evaluated the uptake of [18F]9-fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ), a vesicular monoamine transporter type 2 (VMAT2)-targeting radiotracer, through positron emission tomography (PET) in lactacystin-treated rat brains. METHODS: Adult male Sprague-Dawley rats were randomly treated with a single intracranial dose of lactacystin (2 or 5 μg) or saline (served as the sham control) into the left medial forebrain bundle. A 30-min static [18F]FP-(+)-DTBZ brain PET scan was performed following an intravenous [18F]FP-(+)-DTBZ dose (approximately 22 MBq) in each animal at 2 and 3 weeks after lactacystin treatment. Upon completing the last PET scans, the animals were killed, and their brains were dissected for ex vivo autoradiography (ARG) and immunohistochemical (IHC) staining of tyrosine hydroxylase (TH) as well as VMAT2. RESULTS: Both the 2- and 5-μg lactacystin-treated groups exhibited significantly decreased specific [18F]FP-(+)-DTBZ uptake in the ipsilateral striata (I-ST) at 2 weeks (1.51 and 1.16, respectively) and 3 weeks (1.36 and 1.00, respectively) after lactacystin treatment, compared with the uptake in the corresponding contralateral striata (C-ST) (3.48 and 3.08 for the 2- and 5-μg lactacystin-treated groups, respectively, at 2 weeks; 3.36 and 3.11 for the 2- and 5-μg lactacystin-treated groups, respectively, at 3 weeks) and the sham controls (3.34-3.53). Lactacystin-induced decline in I-ST [18F]FP-(+)-DTBZ uptake was also demonstrated through ex vivo ARG, and the corresponding dopaminergic neuron damage was confirmed by the results of TH- and VMAT2-IHC studies. CONCLUSIONS: In this PD model, lactacystin-induced dopaminergic terminal damage in the ipsilateral striatum could be clearly visualized through in vivo [18F]FP-(+)-DTBZ PET imaging. This may serve as a useful approach for evaluating the effectiveness of new treatments for PD.
Entities:
Keywords:
Animal model; Autoradiography; Lactacystin; PET imaging; Parkinson disease