This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To develop tests to access autonomic dysfunction induced by systemic administration of the neurotoxin 6 hydroxydopamine. PD is associated with loss of autonomic innervation. The heart is one key organ affected. As such, PD patients present heart dysautonomia symptoms like ortostatic hypotension or arrhythmias. Currently, there are not well characterized nonhuman primate models of these problems. Through an interdisciplinary team consisting of PD experts, cardiologists and imaging experts, we are developing a battery of tests to access autonomic dysfunction induced by systemic administration of the neurotoxin 6-hydroxydopamine. Preliminary results from this project suggest that intravenous administration of 6-OHDA induces neurodegeneration of catecholaminergic neurons innervating the heart and can be used to model heart autonomic dysfunction in PD. Progress: Parkinson's disease (PD) is a movement disorder affecting the basal ganglia, yet neurodegeneration also occurs in other areas of the nervous system resulting in dysautonomia, or dysfunction of the autonomic nervous system. Traditional dopamine (DA) replacement therapies for PD patients currently do not provide the relief from them and development of new treatments is difficult due to the lack of animal models. In this study we aimed to develop a cardiac dysautonomia model in rhesus monkeys and generate a toolbox of methods that can be utilized in clinic to assess neurodegeneration in the heart. We hypothesized that the administration of 6-hydroxydopamine 6-OHDA would induce cardiac dysfunction in the monkeys through neurodegeneration of the ganglionic catecholaminergic neurons innervating the heart. Two adult male rhesus monkeys (ages 5-7 yrs old, 7-9kg) were evaluated before and after intravenous administration of 6-OHDA through clinical evaluations, EKG, ultrasound, blood pressure monitoring, troponin and catecholamine blood chemical assays. In addition, in vivo monitoring of neurodegeneration of catecholaminergic terminals in the heart was achieved with positron emission tomography (PET) using the nor-epinephrine analog 11C-meta-Hydroxyephedrine (MHED). Baseline PET scans of the two normal monkeys displayed normal MHED uptake in the heart wall. PET images obtained 7 days post 6-OHDA revealed an extensive decrease in MHED uptake, which confirms loss of catecholaminergic terminals. These preliminary results suggest that intravenous administration of 6-OHDA induces neurodegeneration of catecholaminergic neurons innervating the heart and can be used to model heart autonomic dysfunction in PD. This research uses WNPRC Assay Services and CPI. A publication is in preparation.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000167-50
Application #
8358232
Study Section
Special Emphasis Panel (ZRR1-CM-8 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
50
Fiscal Year
2011
Total Cost
$7,837
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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