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.
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.
authors.affiliation: Imperial College Ophthalmology Research Group (ICORG), Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.|Western Eye Hospital, Imperial College Healthcare NHS Trust, London, UK.|UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Eduardo Maria
authors.initials: EM
authors.lastname: Normando
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Benjamin Michael
authors.initials: BM
authors.lastname: Davis
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.|Neural Circuit Development and Regeneration Research Group, Department of Biology, University of Leuven, Leuven, Belgium.
authors.forename: Lies
authors.initials: L
authors.lastname: De Groef
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Shereen
authors.initials: S
authors.lastname: Nizari
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Turner
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Ravindran
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Milena
authors.initials: M
authors.lastname: Pahlitzsch
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brenton
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Malaguarnera
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Li
authors.initials: L
authors.lastname: Guo
authors.affiliation: School of Pharmacy, University of London, London, UK.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Somavarapu
authors.affiliation: Imperial College Ophthalmology Research Group (ICORG), Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK. m.cordeiro@ucl.ac.uk.|Western Eye Hospital, Imperial College Healthcare NHS Trust, London, UK. m.cordeiro@ucl.ac.uk.|UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK. m.cordeiro@ucl.ac.uk.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Cordeiro
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005500:Follow-Up Studies; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D012160:Retina / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology; D000077154:Rosiglitazone; D012402:Rotenone; D054063:Superior Sagittal Sinus; D045162:Thiazolidinediones / Q000494:pharmacology*; D041623:Tomography, Optical Coherence
chemical_list: D000978:Antiparkinson Agents; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D012402:Rotenone; D000077154:Rosiglitazone
keywords: DARC; Parkinson’s disease; Retina; Rosiglitazone; Rotenone