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Advanced glycation end products can induce glial reaction and neuronal degeneration in retinal explants

¹ INSERM-U592, Laboratory of Retinal Cellular and Molecular Physiopathology, Paris, France
² Department of Ophthalmology, Rouen University Hospital Charles Nicolle, Rouen, France
³ Department of Ophthalmology, Lariboisière Hospital, Paris, France

Correspondence to:
Correspondence to:
Dr Serge Picaud
INSERM-U592, Laboratory of Retinal Cellular and Molecular Physiopathology, Bâtiment Kourilsky, 184 rue du Faubourg Saint-Antoine, 75571 Paris cedex 12, France; picaud{at}st-antoine.inserm.fr

ABSTRACT
Background/aims: Neuronal degeneration has been reported to occur in diabetic retinopathy before the onset of detectable microvascular abnormalities. To investigate whether advanced glycation end products (AGE) could be directly responsible for retinal neurodegeneration, retinal explants were incubated with glycated bovine serum albumin (BSA).

Methods: Retinal explants obtained from non-diabetic adult rats were incubated 4 days with or without 200 µg/ml glycated BSA. Neural apoptosis was quantified by terminal dUTP nick end labelling (TUNEL) binding and immunostaining with anti-cleaved caspase-3 antibody. Expression of glial fibrillary acidic protein (GFAP) was localised by immunofluorescence.

Results: TUNEL and cleaved caspase-3 positive cells increased significantly by 2.2-fold and 2.5-fold in retinal explants incubated in glycated BSA (p<0.05), respectively. The ganglion cell layer was the most sensitive retinal layer to the glycated BSA. Neuronal degeneration was confirmed by the increased GFAP labelling in Müller glial cells from retinal explants treated with glycated BSA.

Conclusion: These results suggest that AGE could induce retinal neurodegeneration in the absence of blood perfusion. Cells in the ganglion cell layer appeared to be the most sensitive as in diabetic retinopathy and its animal models. AGE toxicity could therefore contribute to the early pathological mechanisms of diabetic retinopathy.

Abbreviations: AGE, advanced glycation end products; BSA, bovine serum albumin; DAPI, diamidino-phenyl-indole; DR, diabetic retinopathy; GCL, ganglion cell layer; GFAP, glial fibrillary acidic protein; GLAST, L-glutamate/L-aspartate transporter antibody; INL, inner nuclear layer; ONL, outer nuclear layer; OPL, outer plexiform layer; RAGE, AGE receptor; RPE, retinal pigment epithelium; TUNEL, terminal dUTP nick end labelling; VEGF, vascular endothelium growth factor

Keywords: advanced glycation end products; diabetic retinopathy; glial reaction; neuronal apoptosis; rat

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