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The retina as an early biomarker of neurodegeneration in a rotenone-induced model of Parkinson's disease: evidence for a neuroprotective effect of rosiglitazone in the eye and brain

Title: The retina as an early biomarker of neurodegeneration in a rotenone-induced model of Parkinson's disease: evidence for a neuroprotective effect of rosiglitazone in the eye and brain
Authors: Normando, EM
Davis, BM
De Groef, L
Nizari, S
Turner, LA
Ravindran, N
Pahlitzsch, M
Brenton, J
Malaguarnera, G
Guo, L
Somavarapu, S
Cordeiro, MF
Item Type: Journal Article
Abstract: Parkinson’s Disease (PD) is the second most common neurodegenerative disease worldwide, affecting 1 % of the population over 65 years of age. Dopaminergic cell death in the substantia nigra and accumulation of Lewy bodies are the defining neuropathological hallmarks of the disease. Neuronal death and dysfunction have been reported in other central nervous system regions, including the retina. Symptoms of PD typically manifest only when more than 70 % of dopaminergic cells are lost, and the definitive diagnosis of PD can only be made histologically at post-mortem, with few biomarkers available. In this study, a rotenone-induced rodent model of PD was employed to investigate retinal manifestations in PD and their usefulness in assessing the efficacy of a novel therapeutic intervention with a liposomal formulation of the PPAR-γ (Peroxisome proliferator-activated receptor gamma) agonist rosiglitazone. Retinal assessment was performed using longitudinal in vivo imaging with DARC (detection of apoptosing retinal cells) and OCT (optical coherence tomography) technologies and revealed increased RGCs (Retinal Ganglion Cells) apoptosis and a transient swelling of the retinal layers at day 20 of the rotenone insult. Follow-up of this model demonstrated characteristic histological neurodegenerative changes in the substantia nigra and striatum by day 60, suggesting that retinal changes precede the “traditional” pathological manifestations of PD. The therapeutic effect of systemic administration of different formulations of rosiglitazone was then evaluated, both in the retina and the brain. Of all treatment regimen tested, sustained release administration of liposome-encapsulated rosiglitazone proved to be the most potent therapeutic strategy, as evidenced by its significant neuroprotective effect on retinal neurons at day 20, and on nigrostriatal neurons at day 60, provided convincing evidence for its potential as a treatment for PD. Our results demonstrate significant retinal changes occurring in this model of PD. We show that rosiglitazone can efficiently protect retinal neurons from the rotenone insult, and that systemic administration of liposome-encapsulated rosiglitazone has an enhanced neuroprotective effect on the retina and CNS (Central Nervous System). To our knowledge, this is the first in vivo evidence of RGCs loss and early retinal thickness alterations in a PD model. Together, these findings suggest that retinal changes may be a good surrogate biomarker for PD, which may be used to assess new treatments both experimentally and clinically.
Issue Date: 18-Aug-2016
Date of Acceptance: 11-Jul-2016
URI: http://hdl.handle.net/10044/1/63309
DOI: https://dx.doi.org/10.1186/s40478-016-0346-z
ISSN: 2051-5960
Publisher: BioMed Central
Journal / Book Title: Acta Neuropathologica Communications
Volume: 4
Issue: 1
Copyright Statement: © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Keywords: Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
Parkinson's disease
Rotenone
Retina
Rosiglitazone
DARC
OPTICAL COHERENCE TOMOGRAPHY
PPAR-GAMMA AGONIST
ENDOPLASMIC-RETICULUM STRESS
DOPAMINERGIC-NEURONS
ANIMAL-MODELS
OCULAR HYPERTENSION
PESTICIDE EXPOSURE
CELL APOPTOSIS
INDUCED DEATH
MOUSE MODEL
Parkinson’s disease
Animals
Antiparkinson Agents
Brain
Cell Survival
Cells, Cultured
Disease Progression
Drug Evaluation, Preclinical
Follow-Up Studies
Neuroprotective Agents
PPAR gamma
Parkinsonian Disorders
Rats
Superior Sagittal Sinus
Thiazolidinediones
Tomography, Optical Coherence
Publication Status: Published
Article Number: 86
Online Publication Date: 2016-08-18
Appears in Collections:Division of Surgery
Faculty of Medicine



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