Abstract
Purpose :
Multiple pathophysiological mechanisms are shared across neurodegenerative diseases, including progressive neuronal dysfunction, mitochondrial/metabolic abnormalities, and neuroinflammation. In Parkinson’s disease patients, in addition to degeneration within the substantia nigra, there are functional and histological changes in the retina which might serve as biomarkers for disease and provide metrics for assessing treatment efficacy. 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson’s disease in animals. MPTP is mitochondrial toxin that is taken into the cell by dopamine transporter and when systematically administered induces changes in the retina. This study aimed to assess the effect of direct (intravitreal injection) MPTP administration to the retina. We hypothesized that an injection localized to the eye may produce a retina-only phenotype to facilitate the study of Parkinson’s disease without systemic complications.
Methods :
We assessed the effects of MPTP (5 and 50 mg/mL) via intravitreal injection to C57BL/6J mice. Retinas were analyzed at day 7, 14 and 21 post-injection and assessed by retinal immunofluorescent labelling. The following were quantified: retinal thickness and layer densities, total cell counts (DAPI), retinal ganglion cells (RBPMS, NFM), amacrine cells (CHAT and Prox1), dopaminergic (D1) amacrine cells (tyrosine hydroxylase), and markers of neuroinflammation (IBA1, GFAP, GS). To assess whether this model could be used for neuroprotection studies, an additional cohort was treated with oral nicotinamide (500 mg/kg/d).
Results :
Intravitreal injection of MPTP induced early retinal neuroinflammation in addition to retinal ganglion cell degeneration at all time points investigated relative to naïve and vehicle injected controls. Nicotinamide provided a robust neuroprotection at 21 days post injection in this model.
Conclusions :
Taken together these results indicate that intravitreal MPTP drives a progressive inner retinal degeneration that expands the toolbox for exploring neurodegeneration in Parkinson’s disease. This model does not induce a severe systemic phenotype making it a more accessible model for researchers. Importantly nicotinamide showed robust neuroprotection and potentially offers an exciting avenue for addressing alterations in vision in Parkinson’s disease.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.