Back to Journals » Journal of Inflammation Research » Volume 7

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

Authors Joers V, Vermilyea S, Dilley K, Emborg M

Received 6 May 2014

Accepted for publication 16 June 2014

Published 18 September 2014 Volume 2014:7 Pages 139—149


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Valerie Joers,1,2 Scott Vermilyea,1,2 Kristine Dilley,1 Marina E Emborg1–3

1Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, 2Neuroscience Training Program, 3Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA

Background: We 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.
Methods: Brain 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.
Results: Neither 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.
Conclusion: Our 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.

Keywords: 6-hydroxydopamine, blood–brain barrier, nonhuman primates, neuroinflammation, parkinsonism

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]