Abstract
Current therapies that target vascular endothelial growth factor (VEGF) have become a mainstream therapy for the management of diabetic macular oedema. The treatment involves monthly repeated intravitreal injections of VEGF inhibitors. VEGF is an important growth factor for many retinal cells, including different types of neurons. In this study, we investigated the adverse effect of multiple intravitreal anti-VEGF injections (200 ng/μl/eye anti-mouse VEGF164, once every 2 weeks totalling 5–6 injections) to retinal neurons in Ins2Akita diabetic mice. Funduscopic examination revealed the development of cotton wool spot-like lesions in anti-VEGF treated Ins2Akita mice after 5 injections. Histological investigation showed focal swellings of retinal nerve fibres with neurofilament disruption. Furthermore, anti-VEGF-treated Ins2Akita mice exhibited impaired electroretinographic responses, characterized by reduced scotopic a- and b-wave and oscillatory potentials. Immunofluorescent staining revealed impairment of photoreceptors, disruptions of synaptic structures and loss of amacrine and retinal ganglion cells in anti-VEGF treated Ins2Akita mice. Anti-VEGF-treated WT mice also presented mild amacrine and ganglion cell death, but no overt abnormalities in photoreceptors and synaptic structures. At the vascular level, exacerbated albumin leakage was observed in anti-VEGF injected diabetic mice. Our results suggest that sustained intraocular VEGF neutralization induces retinal neurodegeneration and vascular damage in the diabetic eye.
Highlights
Diabetic retinopathy (DR) affects almost 80% of individuals who have had diabetes for 1–2 decades[1,2]
Following 5 injections, multiple whitish “cotton wool spot (CWS)”-like lesions were observed in 80% of the eyes in anti-vascular endothelial growth factor (VEGF) treated Ins2Akita mice (Fig. 1f)
These whitish lesions were observed at the superficial layer (i.e. nerve fibre layer (NFL)) of the retina and on top of retinal vessels, and were spread in all retinal sectors varying in size from 1⁄4 to 2 optic disc (OD) diameters
Summary
Diabetic retinopathy (DR) affects almost 80% of individuals who have had diabetes for 1–2 decades[1,2]. The therapy reduces neovascular lesion and improves vision, there is a high incidence of retinal geographic atrophy characterised by RPE damage and photoreceptor cell death following the therapy[24] These observations suggest that sustained VEGF depletion may pose severe adverse effects to the human retina. It is crucial to understand the long-term adverse effects of the therapy in patients with DR In support of this concern, a recent study by Park et al.[25] showed that intravitreal injection of a single dose of anti-VEGF resulted in increased inner retinal neuronal degeneration in diabetic rats. We investigated the long-term adverse effects of multiple intravitreal anti-VEGF injections in the Ins2Akita mouse, a model of type 1-diabetes[26]
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