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Validation of a novel progressive rat model of Parkinson’s disease using in vivo positron emission tomography, behavioural assessments, and in vitro autoradiography

University of British Columbia

Parkinson’s disease (PD) is an incurable and progressive neurodegenerative disorder that primarily affects the motor system. PD patients also experience a wide range of non-motor symptoms. Despite many pharmacological treatments demonstrating neuroprotective properties in animal models, most fail to translate to successful clinical trial outcomes. This is partly due to the animal models that are being used to test the treatments. These models are either acute in nature or are able to reproduce primarily only the motor symptoms of PD. Time-limited consumption of β-sitosterol β-D-glucoside (BSSG), a component of the cycad seed, was shown to induce a progressive development of motor, non-motor, and histopathological features in rats that resemble to those observed in PD patients [1,2]. As part of a multi-center validation study, we employed behavioural assessments, in vivo positron emission tomography (PET), and in vitro autoradiography to further characterize the BSSG model. Rats were fed flour pellets or flour pellets containing 3mg of BSSG for 4 months. They were either sacrificed at the end of the BSSG feeding period or maintained for 6 additional months. Behavioural assessments including open field test, olfactory discrimination test, and cylinder test were conducted at baseline, 4 and 10 months following the initial BSSG exposure. No group differences were detected in any behavioural measures over time. PET images acquired using a radioactive tracer that labels dopamine terminals, [¹¹C]DTBZ, also demonstrated no group differences in the nigrostriatal system over time. Autoradiography using [³H]DTBZ, a tritiated analogue to the PET tracer, corroborated the PET findings. Additional autoradiographic experiments using a marker of neuroinflammation, [³H]PBR28, did not demonstrate group differences in the striatum and substantia nigra pars compacta at 4 and 10 months. There were also no group differences in gut microbiota composition during and following BSSG feeding. Our findings were replicated at two other laboratories receiving the pre-manufactured pellets from the same source. However, other independent investigators using the BSSG powder from the same source, but not the pre-made BSSG pellets, were able to replicate many of the original findings. The chemical composition of the BSSG pellets is being questioned and an investigation is under way.

Text

2019-10-01

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71811

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/