Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

Valerie Joers; Kristine Dilley; Shahrose Rahman; Corinne Jones; Jeanette Shultz; Heather Simmons; Marina E. Emborg

doi:10.1371/journal.pone.0104850

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Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

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Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

Valerie Joers, Kristine Dilley, Shahrose Rahman, Corinne Jones, Jeanette Shultz, Heather Simmons and Marina E. Emborg

PloS one, Vol.9(8), p.e104850

08/18/2014

DOI: 10.1371/journal.pone.0104850

PMID: 25133405

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Abstract

Cardiac sympathetic neurodegeneration and dysautonomia affect patients with sporadic and familial Parkinson's disease (PD) and are currently proposed as prodromal signs of PD. We have recently developed a nonhuman primate model of cardiac dysautonomia by iv 6-hydroxydopamine (6-OHDA). Our in vivo findings included decreased cardiac uptake of a sympathetic radioligand and circulating catecholamines; here we report the postmortem characterization of the model. Ten adult rhesus monkeys (5-17 yrs old) were used in this study. Five animals received 6-OHDA (50 mg/kg iv) and five were age-matched controls. Three months post-neurotoxin the animals were euthanized; hearts and adrenal glands were processed for immunohistochemistry. Quantification of immunoreactivity (ir) of stainings was performed by an investigator blind to the treatment group using NIH ImageJ software (for cardiac bundles and adrenals, area above threshold and optical density) and MBF StereoInvestigator (for cardiac fibers, area fraction fractionator probe). Sympathetic cardiac nerve bundle analysis and fiber area density showed a significant reduction in global cardiac tyrosine hydroxylase-ir (TH; catecholaminergic marker) in 6-OHDA animals compared to controls. Quantification of protein gene protein 9.5 (pan-neuronal marker) positive cardiac fibers showed a significant deficit in 6-OHDA monkeys compared to controls and correlated with TH-ir fiber area. Semi-quantitative evaluation of human leukocyte antigen-ir (inflammatory marker) and nitrotyrosine-ir (oxidative stress marker) did not show significant changes 3 months post-neurotoxin. Cardiac nerve bundle alpha-synuclein-ir (presynaptic protein) was reduced (trend) in 6-OHDA treated monkeys; insoluble proteinase-K resistant alpha-synuclein (typical of PD pathology) was not observed. In the adrenal medulla, 6-OHDA monkeys had significantly reduced TH-ir and aminoacid decarboxylase-ir. Our results confirm that systemic 6-OHDA dosing to nonhuman primates induces cardiac sympathetic neurodegeneration and loss of catecholaminergic enzymes in the adrenal medulla, and suggests that this model can be used as a platform to evaluate disease-modifying strategies aiming to induce peripheral neuroprotection.

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Title: Subtitle: Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates
Creators: Valerie Joers - University of Wisconsin System
Kristine Dilley - University of Wisconsin–Madison
Shahrose Rahman - University of Wisconsin–Madison
Corinne Jones - University of Wisconsin–Madison
Jeanette Shultz - University of Wisconsin–Madison
Heather Simmons - University of Wisconsin–Madison
Marina E. Emborg - University of Wisconsin–Madison
Resource Type: Journal article
Publication Details: PloS one, Vol.9(8), p.e104850
DOI: 10.1371/journal.pone.0104850
PMID: 25133405
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library Science
Number of pages: 16
Grant note: R21NS084158 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) P51RR000167; R21NS084158; R01HD15433 / WNPRC NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P51OD011106 / OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HD015433 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) Graduate School of the University of Wisconsin, Madison UW NIH-CTSA P51RR000167 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR)
Language: English
Date published: 08/18/2014
Academic Unit: Communication Sciences and Disorders
Record Identifier: 9985217136102771

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