The Pathogenesis and Therapeutic Approaches of Diabetic Neuropathy in the Retina

Abstract

Diabetic retinopathy is a major retinal disease and a leading cause of blindness in the world. Diabetic retinopathy is a neurovascular disease that is associated with disturbances of the interdependent relationship of cells composed of the neurovascular units, i.e., neurons, glial cells, and vascular cells. An impairment of these neurovascular units causes both neuronal and vascular abnormalities in diabetic retinopathy. More specifically, neuronal abnormalities including neuronal cell death and axon degeneration are irreversible changes that are directly related to the vision reduction in diabetic patients. Thus, establishment of neuroprotective and regenerative therapies for diabetic neuropathy in the retina is an emergent task for preventing the blindness of patients with diabetic retinopathy. This review focuses on the pathogenesis of the neuronal abnormalities in diabetic retina including glial abnormalities, neuronal cell death, and axon degeneration. The possible molecular cell death pathways and intrinsic survival and regenerative pathways are also described. In addition, therapeutic approaches for diabetic neuropathy in the retina both in vitro and in vivo are presented. This review should be helpful for providing clues to overcome the barriers for establishing neuroprotection and regeneration of diabetic neuropathy in the retina.

Optic Nerve Regeneration in Diabetic Retinopathy: Potentials and Challenges Ahead

“…Although the exact pathogenesis of RGC loss in DR is still unclear, recent studies have already found a number of clues mediating this process, reviewed by Potilinski et al and Soni et al [ 16 , 17 ]. In brief, RGC apoptosis occurs in the early stage of DR, induced primarily by oxidative stress, extracellular glutamate accumulation and expression alterations of cytokines and neurotrophic factors ( Figure 1 ) [ 19 ]. In addition, ATP-gated cation channels, such as the P2X7 receptor (P2X7R), may also be the targets for RGC death after early-phase injury [ 23 ].…”

“…As a part of the central nervous system (CNS), adult mammalian RGCs cannot proliferate or regrow, and their axons have little capacity to regenerate following damage, which in clinics leads patients to irreversible vision loss. In the past few decades, tremendous study progress has been made in elucidating mechanisms mediating RGC survival using animal models of DM [ 16 , 17 , 18 , 19 ] and in finding regulators of axon regeneration in models of optic nerve injury [ 20 , 21 , 22 ]. In this review, we discuss potential factors modulating optic nerve regeneration strategies in DR by drawing references from studies using optic nerve injury models.…”

Neurovascular Impairment and Therapeutic Strategies in Diabetic Retinopathy

“…The NVUs are composed of neurons (ganglion cells, amacrine cells, bipolar cells, and horizontal cells), glial cells (Müller cells, astrocytes, and microglia) and vascular cells (endothelial cells and pericytes) [ 19 , 20 , 21 ]. The anatomical and functional interdependence of these cells help to maintain retinal homeostasis and function under healthy conditions.…”

“…In fact, most studies suggest that neuronal changes precede the vascular changes in the clinical findings of the retinas of diabetic patients [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Because neuronal cell death is irreversible and directly related to vision loss, neuroprotection is required to prevent the development and the progression of diabetic neuropathy in the retina at the early stage of diabetic retinas [ 19 , 20 ]. This review focuses on the pathological changes of the NVUs and possible therapeutic options for neuroprotection and vasoprotection of diabetic retinopathy.…”

The pathophysiological mechanisms underlying diabetic retinopathy

“…Thus, blood vessels and nerves are inextricably linked. We should thus not define DR from a single perspective but should consider the interrelationships between multiple factors for a full understanding of the complexity of this disease ( Oshitari, 2021 ).…”