Progress in Neuro-Psychopharmacology and Biological Psychiatry
A new view of diabetic retinopathy: a neurodegenerative disease of the eye
Introduction
Neurodegeneration is recognized as a pivotal feature of many diseases of the central nervous system. It is also recognized as a component of some retinal diseases including glaucoma and retinitis pigmentosa Kerrigan et al., 1997, Baumgartner, 2000, but has been largely overlooked in diabetic retinopathy (DR) despite the degree of vision loss associated with this disease. DR is a common complication of diabetes that is present to some degree in nearly all individuals who have had diabetes for more than 15 years, regardless of whether the diabetes is due to loss of insulin secretion (Type I) or to insulin resistance (Type II) (Klein et al., 1984). It is the leading cause of new cases of legal blindness (defined as vision worse than 20/200) in Americans between the ages of 20 and 74 years (Klein and Klein, 1995).
One of the earliest clinically detectable signs of DR is increased vascular permeability, due to a breakdown in the blood–retinal barrier, which causes macular edema (Cunha-Vaz et al., 1975). This is followed later by the development of vascular microaneurysms, deposition of lipoprotein exudates called drusen, and finally vascular proliferation (Aiello et al., 1998). Of these clinical features, macular edema is most closely correlated with the degree of vision loss (Moss et al., 1988), but the actual relationship between vascular permeability and loss of neural function is not known.
The current treatment for DR is photocoagulation, in which laser flashes are used to burn the areas of retina containing leaking blood vessels (L'Esperance, 1968). This treatment arrests the course of the disease in about 50% of cases but cannot reverse vision loss and must be repeated in many individuals (Blankenship, 1991). In actuality, laser photocoagulation can be likened to amputation because it destroys the diseased parts of the retina in an attempt to rescue less affected regions. Since the development of laser surgery for DR, there have been no major advances in treatment for the disease, despite numerous clinical trials on a variety of drugs including calcium dobesylate, aspirin, aldose reductase inhibitors, and antihistamines Daubresse et al., 1977, Anonymous, 1991, Arauz-Pacheco et al., 1992, Gardner et al., 1995.
Much research has focused on vascular endothelial growth factor (VEGF) because this potent biogenic permeability factor is elevated in the vitreous of people with DR and in animal models of diabetes Aiello et al., 1994, Ambati et al., 1997, Sone et al., 1997, and is sufficient to increase both vascular proliferation and permeability (Aiello et al., 1997). VEGF is produced by the neurons and glial cells of the retina in response to hypoxia, but it is not clear if this is the signal that triggers its expression in diabetes Neufeld et al., 1999, Murata et al., 1996, Amin et al., 1997.
The vascular changes in DR have been given much attention but it is becoming clear that the retinal parenchyma is also altered by diabetes. These changes are reminiscent of chronic neurodegenerative diseases, and include increased apoptosis, a gradual loss of neurons, altered expression of glial fibrillary acidic protein (GFAP) in the astrocytes and Müller cells, and activation of microglia. The following review will attempt to summarize the current evidence supporting the hypothesis that chronic neurodegeneration is a component of DR.
Section snippets
Early clinical changes in vision
While there has been an emphasis on studying the changes to the retinal vasculature in diabetes, pieces of evidence that retinal function is altered soon after the onset of diabetes have also accumulated. Functional changes can be identified before major vascular pathology develops, suggesting that they are due to a direct effect of diabetes on the neural retina, rather than secondary to the breakdown of the blood–retinal barrier (Lieth et al., 2000a).
The electroretinogram (ERG) is a measure of
Evidence of apoptosis in DR
Even before the concept that cells can undergo an active form of destruction called apoptosis, early studies described pyknotic bodies in histological sections of retina from people with diabetes. Pyknosis of neuronal cell bodies was first noted in sections of postmortem eyes from people with diabetes about 40 years ago Wolter, 1961, Bloodworth, 1962. More recently, apoptosis of neurons was observed by in situ terminal dUTP nick end labeling (TUNEL) in sections of retinas from rats treated with
Diabetes increases apoptosis in the retina
To determine whether diabetes increases retinal apoptosis, we adapted the method of TUNEL labeling to whole retinas that were flat-mounted onto microscope slides Barber et al., 1998, Bien et al., 1999. We found that the number of apoptotic nuclei was elevated after 1 month of streptozotocin-induced diabetes. The amount of apoptosis was reduced by intensive treatment with subcutaneous insulin implants, showing that it was a result of the diabetic physiology and not due to toxic effects of the
VEGF as a survival factor for neurons
A great deal of effort has been focused on VEGF because it is elevated in DR and causes both proliferation and increased permeability in vascular endothelial cells Aiello et al., 1994, Ambati et al., 1997. The increased permeability may, in part, be due to a modification of tight junction proteins in the blood–retinal barrier Antonetti et al., 1998, Antonetti et al., 1999. VEGF can also facilitate survival of both endothelial cells and neurons.
VEGF acts as a survival factor for newly formed
Neurofilament changes in DR
During neurodegeneration in the central nervous system, structural changes may occur in neurons that compromise their function but precede actual cell loss. Increased phosphorylation of neurofilament proteins, structural components in the cell bodies, and axons of large neurons such as retinal ganglion cells is associated with axotomy and neurodegeneration Glass and Griffin, 1991, Terada et al., 1998. Decreased neurofilament mRNA and increased phosphorylation have been identified in peripheral
Diabetes causes glial reactivity in the retina
Neurodegeneration also tends to be accompanied by reactive changes in macroglia. The retina has two types of macroglial cells. The predominant type is the Müller cell, which is unique to the retina. Müller cells are spindle-shaped and span the entire retina from the outer limiting membrane to the retinal ganglion cell layer. The second type is the astrocyte, which migrates into the retina along the optic nerve during development Watanabe and Raff, 1988, Ling et al., 1989. Astrocytes are less
Glutamate excitotoxicity as a possible inducer of retinal neurodegeneration in diabetes
Neuronal cell loss in the central nervous system is often associated with excessive levels of glutamate Zorumski and Olney, 1993, Weiss and Sensi, 2000. Several lines of evidence indicate that glutamate excitotoxicity is responsible for the neuronal loss in DR. A number of studies suggest that diabetes increases the concentration of glutamate in the vitreous Ambati et al., 1997, Lieth et al., 1998, Kowluru et al., 2001. Diabetes also reduces the ability of explant retinas to convert [14
Conclusion
It is clear that increased vascular permeability and vascular proliferation is only one component of a complex disease that affects many cell types within the retina. DR has many elements that suggest chronic neurodegeneration, including: neural apoptosis, loss of ganglion cell bodies, reduction in thickness of the inner retina, glial reactivity, neurofilament abnormality, slowing of optic nerve retrograde transport, changes in electrophysiological activity, and resultant deficits in
Acknowledgements
The author would like to thank past and present members of the Penn State Retina Research Group who contributed to the ideas expressed in this work, particularly Thomas W. Gardner, David A. Antonetti, Erich Lieth, and Kathryn F. LaNoue. The author also acknowledges financial support from the Fight for Sight, the Pennsylvania Lions Sight Conservation and Eye Research Foundation, and the Juvenile Diabetes Research Foundation.
References (93)
- et al.
Synergistic action of thyroid hormone, insulin and hydrocortisone on astrocyte differentiation
Brain Res.
(1987) - et al.
Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occludin-1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors
J. Biol. Chem.
(1999) - et al.
The effect of the aldose reductase inhibitor, ponalrestat, on the progression of diabetic retinopathy
J. Diabetes Complicat.
(1992) - et al.
Glutamate enhances phosphorylation of neurofilaments in cerebellar granule cell culture
J. Neurol. Sci.
(1999) - et al.
Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-Kinase/Akt-mediated mechanism that reduces the activation of Caspase-3
J. Biol. Chem.
(2001) Etiology, pathogenesis, and experimental treatment of retinitis pigmentosa
Med. Hypotheses
(2000)Fifteen-year argon laser and xenon photocoagulation results of Bascom Palmer Eye Institute's patients participating in the diabetic retinopathy study
Ophthalmology
(1991)- et al.
Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells
J. Biol. Chem.
(1998) - et al.
Function of leucine in excitatory neurotransmitter metabolism in the central nervous system
J. Nutr.
(2001) - et al.
The cellular and molecular mechanisms of diabetic complications
Endocrinol. Metab. Clin. N. Am.
(1996)
Retinal glutamate in diabetes and effect of antioxidants
Neurochem. Int.
NMDA and AMPA glutamate receptor subtypes in the thoracic spinal cord in lean and obese–diabetic ob/ob mice
Brain Res.
Hippocampal neuronal apoptosis in type 1 diabetes
Brain Res.
Diabetes reduces glutamate oxidation and glutamine synthesis in the retina
Exp. Eye Res.
The incidence of vision loss in a diabetic population
Ophthalmology
Excessive hexosamines block the neuroprotective effect of insulin and induce apoptosis in retinal neurons
J. Biol. Chem.
Antigens associated with specific retinal cells are affected by ischaemia caused by raised intraocular pressure: effect of glutamate antagonists
Neurochem. Int.
Bax is increased in the retina of diabetic subjects and is associated with pericyte apoptosis in vivo and in vitro
Am. J. Pathol.
The development of electroretinogram abnormalities and the possible role of polyol pathway activity in diabetic hyperglycemia and galactosemia
Metabolism
Vascular endothelial growth factor inhibits endothelial cell apoptosis induced by tumor necrosis factor-alpha: balance between growth and death signals
J. Mol. Cell. Cardiol.
Delayed Wallerian degeneration and increased neurofilament phosphorylation in sciatic nerves of rats with streptozocin-induced diabetes
J. Neurol. Sci.
Ca2+–Zn2+ permeable AMPA or kainate receptors: possible key factors in selective neurodegeneration
TINS
Structure–function relationships of insulin receptor interactions in cultured mouse astrocytes
Brain Res.
Excitotoxic neuronal damage and neuropsychiatric disorders
Pharmacol. Ther.
Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders
N. Engl. J. Med.
Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor
Diabetes
Diabetic retinopathy
Diabetes Care
Changes in vitreal oxygen tension distribution in the streptozotocin diabetic rat
Diabetologia
Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity
Nat. Med.
Elevated gamma-aminobutyric acid, glutamate, and vascular endothelial growth factor levels in the vitreous of patients with proliferative diabetic retinopathy
Arch. Ophthalmol.
Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy
Invest. Ophthalmol. Vis. Sci.
Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Early Treatment Diabetic Retinopathy Study Research Group
Ophthalmology
Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells
Diabetes
Impaired contrast sensitivity in adolescents and young type 1 (insulin-dependent) diabetic patients with microalbuminuria
Acta Ophthalmol. (Copenhagen)
Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin
J. Clin. Invest.
Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes
Invest. Ophthalmol. Vis. Sci.
Apoptotic versus necrotic characteristics of retinal ganglion cell death after partial optic nerve injury
J. Neurotrauma
The radial glia of Müller in the rat retina and their response to injury. An immunofluorescence study with antibodies to the glial fibrillary acidic (GFA) protein
Exp. Eye Res.
Diabetic retinopathy
Diabetes
Oxygen tension and blood flow in the retina of normal and diabetic rats
Adv. Exp. Med. Biol.
Early breakdown of the blood–retinal barrier in diabetes
Br. J. Ophthalmol.
A controlled clinical trial of calcium dobesylate in the treatment of diabetic retinopathy
Diabetes Metab.
Impaired contrast sensitivity in diabetic patients with and without retinopathy: a new technique for rapid assessment
Br. J. Ophthalmol.
NMDA receptor subunits are modified transcriptionally and post-translationally in the brain of streptozotocin-diabetic rats
Diabetologia
Contrast sensitivity in obese dyslipidemic patients with insulin resistance
Arch. Ophthalmol.
Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy
Diabetes
Cited by (561)
Next generation therapeutics for retinal neurodegenerative diseases
2024, Journal of Controlled ReleaseStudies of the retinal microcirculation using human donor eyes and high-resolution clinical imaging: Insights gained to guide future research in diabetic retinopathy
2023, Progress in Retinal and Eye ResearchCitation Excerpt :These inflammatory cytokines recruit circulating inflammatory cells such as neutrophils and macrophages to infiltrate injured areas and incite further damage. Microglia related neuronal injury is considered to be a contributary mechanism to several clinical manifestations of DR. Retinal neurodegeneration characterised by thinning of the GCL and retinal NFL during early stages of DR was shown to precede microvascular impairment and visual symptoms (Barber, 2003; Kim et al., 2019; Simó and Hernández, 2014; van Dijk et al., 2012). In addition to inner retinal changes, microglia associated IL-6 upregulation was found to facilitate microglia recruitment into the RPE layer.
Ketorolac and (-)-Epicatechin change retinal GFAP and NRF2 expression on hyperglycemic CD1 mice
2023, Journal of NeuroimmunologySingle-cell RNA sequencing reveals roles of unique retinal microglia types in early diabetic retinopathy
2024, Diabetology and Metabolic Syndrome