Purpose: Dry age-related macular degeneration (AMD) is a multifactorial, degenerative retinal-choroidal disease and the leading cause of blindness in the elderly in developed countries. The hallmarks of dry AMD are drusen formation and atrophy of the retinal pigment epithelium (RPE), photoreceptors and choriocapillaris. Exposure to the oxidizing agent sodium iodate (NaIO3) leads to dysfunction and death of RPE cells and secondary, damage of the photoreceptors. This study aimed to characterize the acute rat NaIO3 model, using several non-invasive modalities to investigate morphological and functional changes, complemented with immunohistological analyses.
Methods: NaIO3 (20-50mg/kg) or vehicle (PBS) was administered intraperitoneally (IP) or via the sublingual vein (IV) in 10- to 12-week-old male Brown Norway rats (n=3). Progression of the pathology was evaluated longitudinally via spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) and electroretinography (ERG). RPE intactness (phalloidin), retinal inflammation (Cd11b) and gliosis (glial fibrillary acidic protein, GFAP) were investigated using immunohistochemistry on RPE-choroidal flat mounts and paraffin sections at 7 days post injury (7dpi).
Results: FAF images demonstrated higher variability in the retinopathy after IP administration as compared to IV injection of NaIO3. IV administration of NaIO3 resulted in a clear dose-dependent effect as observed via the presence of RPE degeneration on FAF, reduced scotopic a- and b-wave ERG responses and decreased outer retinal thickness measurements on OCT images. Retinopathy was already visible at early time points after IV 40mg/kg NaIO3 administration: OCT (1dpi), FAF (3dpi) and ERG (3dpi). Moreover, NaIO3 treatment resulted in a significant increase in retinal inflammation (2.5-fold, p<0.01) and gliosis (3.1-fold, p<0.0001) and a severely disrupted RPE integrity, which was less pronounced in the peripheral zone as compared to central and middle areas.
Conclusion: IV administration of 40mg/kg NaIO3 in pigmented rats induced acute morphological and functional changes of the RPE and neuroretina with high reproducibility. As such, this model is appropriate for testing and developing drug candidates for dry AMD through the use of complementary read-out methods.