Neurodegeneration: An early event of diabetic retinopathy

Abstract

Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia. However, retinal neurodegeneration is already present before any microcirculatory abn ormalities can be detected in ophthalmoscopic exa mination. In other words, retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR. Therefore, the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR. Elevated levels of glutamate and the overexpression of the renin angiotensinsystem play an essential role in the neurodegenerative process that occurs in diabetic retina. Among neuroprotective factors, pigment epithelial derived factor, somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review. Nevertheless, it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neu rotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye. New strategies, based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors, are currently being tested in experimental models and in clinical pilot studies. Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research.

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

“…Usually the first sign of the Müller cell stress is upregulation of glial fibrillary acidic protein (GFAP) content, which may be accompanied by hypertrophy and proliferation under certain damaging conditions. Diabetes itself is able to upregulate GFAP in Müller cells without the presence of other symptoms of DR in humans (Villaroel et al, 2010), and this goes along well with what we see in experimental models where after 2 days of diabetes induction, GFAP upregulation is already apparent (K. Szabadfi, unpublished observation). All the aforementioned observations may lead to the formation of a fourth hypothesis of the initiation of DR, the "glial cells-first" scenario.…”

“…The deterioration of the intrinsic time and also of oscillatory potentials (OPs) in the electroretinogram (ERG) starts early, in some cases as early as 2 days after induction of diabetes in experimental animals . These observations led to the formulation of the "neurodegeneration-first" hypothesis (Villaroel et al, 2010). Patients suffering from DR experience gradual vision loss; after ERG deterioration, the visually evoked potentials (VEPs) also start to To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi.…”

Neuroretinal alterations in the early stages of diabetic retinopathy in patients with type 2 diabetes mellitus

“…These are suggested by Barber et al, 5 who showed increased apoptosis of retinal neural cells both in experimental diabetic rats and in diabetic patients. Increased apoptosis is probably due to the following: (i) neurofilament accumulation in RGC axons, related to changes in retrograde axonal transport; 26 (ii) elevated levels of glutamate; (iii) increasing neurotoxic factors, 27 and (iv) reactive changes in microglia. 28 Moreover, comparing patients without abnormalities on the RNFL and GC-IPL analysis with healthy controls, we found a significant GC-IPL and RNFL thickness reduction.…”

Progression of Early Retinal Dysfunction in Diabetes Over Time: Results of a Long-term Prospective Clinical Study

“…Neuronal degeneration patterns have been observed in various animal models of diabetes, and early retinal dysfunction has been demonstrated (3,4). Postmortem studies in humans have revealed neuronal degeneration and apoptosis in retinas, mainly in the ganglion cell layer (5,6).…”