Molecular Mechanisms Mediating Diabetic Retinal Neurodegeneration: Potential Research Avenues and Therapeutic Targets

Diabetic retinopathy (DR) is a devastating complication of diabetes with a prevalence rate of 35%, and no effective treatment options. Since the most visible clinical features of DR are microvascular irregularities, therapeutic interventions often attempt to reduce microvascular injury, but only after permanent retinal damage has ensued. However, recent data suggests that diabetes initially affects retinal neurons, leading to neurodegeneration as an early occurrence in DR, before onset of the more noticeable vascular abnormalities. In this review, we delineate the sequence of initiating events leading to retinal degeneration in DR, considering neuronal dysfunction as a primary event. Key molecular mechanisms and potential biomarkers associated with retinal neuronal degeneration in diabetes are discussed. In addition to glial reactivity and inflammation in the diabetic retina, the contribution of neurotrophic factors, cell adhesion molecules, apoptosis markers, and G protein signaling to neurodegenerative pathways warrants further investigation. These studies could complement recent developments in innovative treatment strategies for diabetic retinopathy, such as targeting retinal neuroprotection, promoting neuronal regeneration, and attempts to re-program other retinal cell types into functional neurons. Indeed, several ongoing clinical trials are currently attempting treatment of retinal neurodegeneration by means of such novel therapeutic avenues. The aim of this article is to highlight the crucial role of neurodegeneration in early retinopathy progression, and to review the molecular basis of neuronal dysfunction as a first step toward developing early therapeutic interventions that can prevent permanent retinal damage in diabetes. ClinicalTrials.gov: NCT02471651, NCT01492400.