Author: Tine Van Bergen (Belgium)
Co-authors: Tine Van Bergen, Inge Van Hove, Alan Stitt, Jean Feyen
Purpose
Age-related macular degeneration (AMD) is a degenerative retinal disease and the leading cause of blindness in the elderly. The late stage of dry AMD, or geographic atrophy (GA), is characterized by extensive retinal pigment epithelium (RPE) degeneration. The use of sodium iodate (NaIO3), a relatively specific oxidant for the RPE, has extensively been used as a pre-clinical model of RPE atrophy. The severe retinal changes in the mouse NaIO3 model have been broadly described in literature, whereas the rat NaIO3 model is less well documented. This study aimed to characterize the retinal histopathological changes of rats injected with NaIO3.
Setting/Venue
The rodent NaIO3 model has emerged as an acute valuable model to study RPE degeneration in GA in a compact time-frame. Characterization of the histopathologic changes in the retina are necessary to understand and validate the NaIO3 model for further drug testing for dry AMD.
Methods
Animals were divided into two groups (n=5-11/group): PBS-injected control rats and NaIO3-injected rats. NaIO3 (40 mg/kg) was administered via the sublingual vein in 9-11-week-old male Brown Norway rats at day 0. At day 7, retinal inflammation (CD11b), gliosis (Glial fibrillary acidic protein: GFAP), RPE (RPE65) and rod bipolar cell (PKC alpha) changes were quantified using immunohistochemistry on 9µm paraffin sections. Positive area of the histological markers in the NaIO3-treated retinas was measured over the total retinal area and presented relative towards the control. RPE/choroidal flat mounts were analyzed after a phalloidin staining for RPE intactness in the peripheral, middle and central area, using a scoring system from 0 (intact cells), 1 (intact and elongated cells), 2 (elongated cells), 3 (elongated cells and atrophy) to 4 (atrophy). Comparisons between the two groups were performed using unpaired Student’s t-tests.
Results
Key markers of retinal inflammation and gliosis were significantly increased after NaIO3 by respectively 2.5-fold (%CD11b+ area in NaIO3: 100 ± 5.47 vs. control: 40.4 ± 6.87, p-value smaller than 0.01) and 3.1-fold (%GFAP+ area in NaIO3: 100 ± 8.8 vs. control: 32.5 ± 4.05, p-value smaller than 0.0001). Increased PKC alpha signal in the rod bipolar cells, indicative of a rewiring process, was also observed in the group treated with NaIO3, as compared to the control group. Analysis of the RPE staining revealed that NaIO3 induced complete RPE damage/loss (score : 3 to 4) in the central/middle areas whereas the periphery remained relatively intact (score : 0 to 2, p-value smaller than 0.0001).
Conlusions
This study demonstrated that sublingual injection of NaIO3 (40 mg/kg) in the rat induced retinal inflammation and gliosis which was consistently accompanied with RPE loss and disruption in the central/middle retinal area whereas the periphery remained relatively intact. As such, the rat NaIO3 model might be a suitable acute model for testing and developing drugs for dry AMD.
Financial Disclosure
Direct financial relationship for Oxurion
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