Effect of glucocorticoids on neuronal and vascular pathology in a transgenic model of selective Müller cell ablation

Abstract

 

Purpose

 

Many retinal diseases exhibit pathological processes that affect both neurons and blood vessels. Treatments that address both at the same time might have advantages over more specific approaches, such as vascular endothelial growth factor (VEGF) inhibitors which are used to treat vascular leak but are suspected to have a neurotoxic effect. The aim of this study was to evaluate the effects of an intravitreal injection of triamcinolone acetonide (TA) in a transgenic model in which patchy Müller cell ablation leads to photoreceptor degeneration, vascular leak and intraretinal neovascularization.

 

Methods

 

TA was injected 4 days before induced Müller cell ablation. Changes in photoreceptors, microglia and Müller cells, differential expression of P75 neurotrophin receptor (p75NTR), tumor necrosis factor-α (TNFα), the precursor and mature forms of neurotrophin 3 (pro-NT3 and NT3) and activation of the p53 and p38 stress-activated protein kinase (p38/SAPK) signalling pathways were examined. We also evaluated the effects of TA on retinal vascular pathology.

 

Results

 

We found that TA prevented photoreceptor degeneration and inhibited reactive activation of microglial and Müller cells. TA also attenuated Müller cell loss and inhibited overexpression of P75NTR, TNFα, pro-NT and the activation of p53 and p38/SAPK signalling pathways. TA not only prevented the development of retinal vascular lesions but also inhibited fluorescein leakage from established vascular lesions. TA inhibited overexpression of VEGF in transgenic mice but without affecting its basal level expression in the normal retina.

 

Conclusions

 

Our data suggest that glucocorticoid treatment may be beneficial for treatment of retinal diseases that affect both neurons and the vasculature.

 

 

Intravitreal injection of triamcinolone acetonide protected photoreceptors concurrently with inhibition of microglial activation. Double labelling was conducted on retinal wholemounts using an antibody against ionized calcium binding adaptor molecule 1 (Iba-1) for microglia (green) and peanut-agglutinin (PNA) for cone photoreceptor outer segments (red) in a transgenic model of selective Muller cell ablation.

 

Keywords: 615 neuroprotection • 648 photoreceptors • 695 retinal degenerations: cell biology