Abstract
Purpose :
Ocular hypertension (OHT) and secondary iatrogenic open angle glaucoma are the serious side effects of glucocorticoid (GC) therapy, which is used widely to treat various immune mediated diseases. We have previously developed a novel mouse model of GC-induced OHT using weekly periocular injections of potent GC, dexamethasone (Dex). The purpose of this study is to examine whether sustained Dex-induced OHT leads to glaucoma phenotype in mice
Methods :
Three-month old C57BL/6J mice (n=30) were injected with either Dex-Acetate (200µg/eye) or vehicle suspension via periocular route, once in a week for 10-weeks. IOP was measured every week and pattern electro retinogram (pERG) was used to measure RGC function at 10-weeks post injections. Alexa Flour 594-cholera toxin B (CTB) was injected intravitreally, to trace the deficits in anterograde axon transport. Abnormal extracellular matrix (ECM) deposition in trabecular meshwork (TM) was assessed by immunostaining. RGC loss was analyzed by whole mount retina staining with RBPMS antibody and axon degeneration was examined by PPD staining.
Results :
Weekly injections of Dex but not vehicle caused sustained and pronounced IOP elevation in mice, starting from 1-week of injection (Δ ≥3.5mmHg IOP). In addition, Dex reduced the outflow facility (~30%) and also induced abnormal ECM proteins (fibronectin and collagen I) deposition in TM. pERG revealed significant deficits in RGCs function as evident from reduced pERG amplitudes (10µV v/s 25 µV) with increased N1 latency periods (140ms v/s 100ms) in Dex-injected mice compared to vehicle injected mice. Importantly, we observed a highly significant RGC loss in Dex-mice (loss was ~60% in periphery and ~50% in mid-periphery). Axon anterograde transport tracer CTB accumulated in ONH of Dex-mice, indicating deficits in axonal transport. PPD-stained cross sections of optic nerves showed severe axonal damage in Dex-mice, whereas no damage was observed in vehicle injected mice
Conclusions :
These data suggest that our novel mouse model of periocular Dex-induced OHT develops glaucoma phenotype. Also, there are many clinical, morphological, and molecular similarities between our Dex-induced glaucoma model and POAG, making this mice model as an attractive model to study the specific aspects of POAG, including TM and RGCs pathology in glaucoma.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.