Diabetic retinopathy: Neuroprotection as a therapeutic target

Diabetic retinopathy (DR) is a multifactorial progressive disease of the retina and a leading cause of vision loss. DR has long been regarded as a vascular disorder, although metabolic alterations result in neuronal death and visual impairment well before the vascular disorders appear. A variety of animal studies and clinical observations documented the important role played by neurodegeneration in the diabetic retina before classical signs of DR are recognizable and suggest that a neuroprotective strategy should be considered for treatment before the appearance of vascular lesions. Major causes of neuronal death in DR are likely to include the formation of advanced glycation end-products, glutamate excitotoxicity, activation of the polyol pathway, oxidative stress, neuroinflammation, and dysregulation of endogenous neuroprotectants. Upregulation of vascular endothelial growth factor (VEGF), which is the main target of current therapies, is likely to be one of the first responses to retinal hyperglycemic stress and VEGF may represent an important survival factor in early phases of DR. Of central importance for clinical trials is the detection of retinal neurodegeneration in the clinical setting. Different techniques are currently available and spectral domain optical coherence tomography seems the most indicated for monitoring neurodegeneration in DR. A plethora of substances have been tested in animal studies for their neuroprotective properties and for possible use in human therapy. Perhaps, the most intriguing perspective is the possibility of using either endogenous neuroprotective substances or nutraceuticals. Together, the data reviewed here point to the central role of neurodegeneration in the pathogenesis of DR and provide a solid basis for proposing neuroprotection as an effective strategy for preventing or arresting DR. However, clinical trials to determine not only the effectiveness and safety, but also the compliance of a non-invasive route of drug administration, as well as a standardization of the methods for monitoring neurodegeneration, are needed.