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.

Caveolins and caveolae in ocular physiology and pathophysiology

“…Cav-1 expression is induced by thiazolidinediones such as rosiglitazone, a PPAR γ agonist used to treat type 2 diabetes (Llaverias et al, 2004; Tencer et al, 2008). In the retina, these compounds suppress retinal and choroidal neovascularization (Higuchi et al, 2010; Murata et al, 2001; Murata et al, 2000), reduce diabetes-induced retinal vascular inflammation and BRB breakdown (Muranaka et al, 2006), and promote neuroprotection (Doonan et al, 2009; Li et al, 2011; Normando et al, 2016). It remains to be determined whether these effects are mediated through Cav-1 expression in the retina.…”

Role of Caveolin-1 in Diabetes and Its Complications

“…Conversely, the in vivo silencing of CAV1 by siRNA in the retina can suppress neovascularization and pathological BRB breakdown in ischemia-induced retinal disease [216]. It is noteworthy to mention that thiazolidinediones or peroxisome proliferator-activated receptorgamma (PPARγ) agonists that are used to treat T2DM, can suppress retinal neovascularization, attenuate retinal vascular inflammation and BRB breakdown, and promote neuroprotection in the retina [217,218]. PPARγ activation induces CAV1 [219] and has all the hallmarks of CAV1 action such as the previously mentioned decrease of insulin resistance, adipocyte regulation, and antiproliferative action [220].…”

Optical coherence tomography in the investigation of systemic neurologic disease

“…Parkinson's disease is a progressive neurodegenerative disorder characterised by loss of nerve cells in the substantia nigra of the brain and accumulation of Lewy bodies (abnormal aggregates of the protein, α‐synuclein) . This in turn results in loss of dopaminergic cells followed by a reduction in the neurotransmitter, dopamine.…”

“…An OCT study in rotenone‐induced rodent models revealed retinal ganglion cell death and a temporary swelling of the retina after 20 days of rotenone insult; however, loss of dopaminergic cells was evident in the substantia nigra only after two months, suggesting that retinal changes may precede cell loss in the brain …”