Nonuniform Cardiac Denervation Observed by 11C-meta-Hydroxyephedrine PET in 6-OHDA-Treated Monkeys

Joers, Valerie; Seneczko, Kailie; Goecks, Nichole; Kamp, Timothy J.; Hacker, Timothy A.; Brunner, Kevin; Engle, Jonathan W.; Barnhart, Todd E.; Nickles, R.J.; Holden, James E.; Emborg, Marina E.

doi:10.1371/journal.pone.0035371

Cited by 22 publications

(61 citation statements)

References 48 publications

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“…We did not find increased PGP9.5 expression in the left ventricle, suggesting that hyperinnervation is unlikely at 3 months following 6-OHDA. In vivo evaluations for cardiac function using an echocardiogram and ECG in 6-OHDA-treated monkeys showed no signs of dysrhythmias, further suggesting the unlikely occurrence of hyperinnervation [29]. Studies with longer timelines are needed to understand if PGP9.5 or TH-immunoreactive fibers increase above baseline levels at timepoints greater than 3 months post-neurotoxin.…”

Section: Discussionmentioning

confidence: 99%

“…The 6-OHDA-treated cardiac and adrenal medulla sections (n = 5; 7.0±1.57 yrs old; 7.35±1.65 kg; 2 male) were from a previously published study [29]. Dosing of 6-OHDA to these monkeys was done in sterile surgical conditions under isofluorane anesthesia, as a sequence of 7–9 intravenous injections totaling a final dose of 50 mg/kg.…”

Section: Methodsmentioning

confidence: 99%

“…Systemic dosing of 6-OHDA induces peripheral sympathetic loss and has been used to model cardiac denervation in rodents [22], [23], [24], [25], dogs [26], [27] and monkeys [28], [29]. Few of these studies have evaluated cardiac sympathetic innervation with in vivo imaging (reviewed in [13]).…”

Section: Introductionmentioning

confidence: 99%

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Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

et al. 2014

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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 α-synuclein-ir (presynaptic protein) was reduced (trend) in 6-OHDA treated monkeys; insoluble proteinase-K resistant α-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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

et al. 2014

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“…Qtc: Surface electrograms were collected from the anesthetized animals. The uncorrected QT interval, R-R interval, heart rate, as well as QT interval data corrected using Bazett’s correction (called QTc = QT in msec/√R-R sec) was calculated on each electrocardiogram for all animals [11,12]. Calipers were used to assess the raw data to determine all ECG intervals.…”

Section: Methodsmentioning

confidence: 99%

IND-Directed Safety and Biodistribution Study of Intravenously Injected Cetuximab-IRDye800 in Cynomolgus Macaques

et al. 2014

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Purpose The use of receptor-targeted antibodies conjugated to fluorophores is actively being explored for real-time imaging of disease states, however, the toxicity of the bioconjugate has not been assessed in non-human primates. Procedures To this end, the in vivo toxicity and pharmacokinetics of IRDye800 conjugated to cetuximab (cetuximab-IRDye800; 21 mg/kg; equivalent to 250 mg/m2 human dose) was assessed in male cynomolgus monkeysover15 days following intravenous injection and compared with an unlabeled cetuximab-dosed control group. Results Cetuximab-IRDye800 was well tolerated. There were no infusion reactions, adverse clinical signs, mortality, weight loss, or clinical histopathology findings. The plasma half-life for the cetuximab-IRDye800 and cetuximab groups were equivalent (2.5 days). The total recovered cetuximab-IRDye800 in all tissues at study termination was estimated to be 12% of the total dose. Both cetuximab-IRDye800 and cetuximab groups showed increased QTc after dosing. The QTc for the cetuximab-dosed group returned to baseline by day 15, while the QTc of the cetuximab-IRDye800 remained elevated compared to baseline. Conclusion IRDye800 in low molar ratios does not significantly impact cetuximab half-life or result in organ toxicity. These studies support careful cardiac monitoring (ECG) for human studies using fluorescent dyes.

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“…We have recently developed a nonhuman primate model of cardiac dysautonomia by systemic dosing of 6-OHDA 17,18. In vivo and post mortem analysis confirmed loss of catecholaminergic innervation in the heart as well as loss of circulating catecholamines produced by the adrenal medulla; motor symptoms of Parkinson’s disease were not observed.…”

Section: Introductionmentioning

confidence: 98%

Systemic administration of 6-OHDA to rhesus monkeys upregulates HLA-DR expression in brain microvasculature

Joers

Vermilyea

Dilley

et al. 2014

JIR

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BackgroundWe recently developed a nonhuman primate model of cardiac dysautonomia by systemic dosing of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA). The aim of this study was to assess whether systemic 6-OHDA affects the central nervous system of nonhuman primates, in particular the dopaminergic nigrostriatal system.MethodsBrain sections from adult rhesus monkeys that received systemic 6-OHDA (50 mg/kg intravenously; n=5) and were necropsied 3 months later, as well as normal controls (n=5) were used in this study. Tissue was cut frozen at 40 μm on a sliding microtome, processed for immunohistochemistry, and blindly evaluated.ResultsNeither the optical density of tyrosine hydroxylase immunoreactivity (TH-ir; a dopaminergic neuronal marker) in the caudate and putamen nucleus nor the TH-ir cell number and volume in the substantia nigra showed significant differences between groups. Yet within groups, statistical analysis revealed significant individual differences in the 6-OHDA-treated group, with two animals showing a lower cell count and volume. Optical density quantification of α-synuclein-ir in the substantia nigra did not show differences between groups. As α-synuclein intracellular distribution was noted to vary between animals, it was further evaluated with a semiquantitative scale. A greater intensity and presence of α-synuclein-positive nigral cell bodies was associated with larger TH-positive nigral cell volumes. Increased human leukocyte antigen (HLA-DR; a microglial marker) expression was observed in 6-OHDA-treated animals compared with controls. HLA-DR-ir was primarily localized in endothelial cells and perivascular spaces throughout cortical and subcortical structures. Semiquantitative evaluation using a rating scale revealed higher HLA-DR-ir in blood vessels of 6-OHDA-treated animals than controls, specifically in animals with the lowest number of dopaminergic nigral neurons.ConclusionOur results demonstrate that systemic 6-OHDA administration to rhesus monkeys can affect the dopaminergic nigrostriatal system and upregulate inflammatory markers in the cerebrovasculature that persist 3 months post neurotoxin challenge. The variability of the subject response suggests differences in individual sensitivity to 6-OHDA.

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Nonuniform Cardiac Denervation Observed by 11C-meta-Hydroxyephedrine PET in 6-OHDA-Treated Monkeys

Cited by 22 publications

References 48 publications

Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

IND-Directed Safety and Biodistribution Study of Intravenously Injected Cetuximab-IRDye800 in Cynomolgus Macaques

Systemic administration of 6-OHDA to rhesus monkeys upregulates HLA-DR expression in brain microvasculature

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