Abstract
Impairment of the ubiquitin proteasome system has been implicated in Parkinson’s disease. We used positron emission tomography to investigate longitudinal effects of chronic intracerebroventricular exposure to the proteasome inhibitor lactacystin on monoaminergic projections and neuroinflammation. Göttingen minipigs were implanted in the cisterna magna with a catheter connected to a subcutaneous injection port. Minipigs were imaged at baseline and after cumulative doses of 200 and 400 μg lactacystin, respectively. Main radioligands included [11C]-DTBZ (vesicular monoamine transporter type 2) and [11C]-yohimbine (α2-adrenoceptor). [11C]-DASB (serotonin transporter) and [11C]-PK11195 (activated microglia) became available later in the study and we present their results in a smaller subset of animals for information purposes only. Striatal [11C]-DTBZ binding potentials decreased significantly by 16% after 200 μg compared to baseline, but the decrease was not sustained after 400 μg (n = 6). [11C]-yohimbine volume of distribution increased by 18–25% in the pons, grey matter and the thalamus after 200 μg, which persisted at 400 μg (n = 6). In the later subset of minipigs, we observed decreased [11C]-DASB (n = 5) and increased [11C]-PK11195 (n = 3) uptake after 200 μg. These changes may mimic monoaminergic changes and compensatory responses in early Parkinson’s disease.
Highlights
Parkinson’s disease (PD) targets the motor system leading to resting tremor, bradykinesia and rigidity as the most characteristic symptoms
We investigate the longitudinal effects of chronic direct intracerebroventricular (ICV) exposure to lactacystin on monoaminergic projections and, in a small subset, on neuroinflammation, using in vivo Positron emission tomography (PET) imaging and specific tracers
Data are presented for one lactacystin-injected minipig vs a control at the level of the LC (Fig. 6c,f). In this proof of concept study, using multi-modal PET imaging, we were able to non-invasively track monoaminergic and inflammatory brain changes in vivo in Göttingen minipigs exposed to sustained ubiquitin proteasome system (UPS) inhibition through a catheter in the cisterna magna coupled to a subcutaneous injection port
Summary
Parkinson’s disease (PD) targets the motor system leading to resting tremor, bradykinesia and rigidity as the most characteristic symptoms. According to the Lewy body-based Braak’s pathology staging of PD, serotonergic (median raphe) and noradrenergic (locus coeruleus (LC)) nuclei located in the brainstem are affected in stage 2 of the disease, while dopaminergic neurons in the substantia nigra (SN) are affected later, in stages 3-43. These changes in non-dopaminergic monoaminergic innervation are suspected to contribute significantly to the multiple non-motor symptoms of the disease, both in prodromal as well as in the manifested clinical condition[2,4]. We explored the neuroinflammatory component of the model using [N-methyl-11C](R)-1-(2-chlorophenyl)-N-(1-methylpropyl)-3-isoquinolinecarboxamide ([11C]-PK11195), a tracer of activated microglia, in a small group of 3 minipigs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
