Targeted pharmacotherapy against neurodegeneration and neuroinflammation in early diabetic retinopathy

• Published in: Neuropharmacology 2021-04, Vol.187, p.108498-108498, Article 108498
• Main Authors: Rolev, Kostadin Dimov, Shu, Xing-sheng, Ying, Ying
• Format: Article
• Language: English
• Subjects: Diabetic retinopathy; Glial cell activation; Glycogen synthase kinase-3β (GSK-3β); Retinal ganglion cells (RGCs); Synaptic neurodegeneration; Tau hyperphosphorylation
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2021.108498

Diabetic retinopathy (DR), the most frequent complication of diabetes, is one of the leading causes of irreversible blindness in working-age adults and has traditionally been regarded as a microvascular disease. However, increasing evidence has revealed that synaptic neurodegeneration of retinal ganglion cells (RGCs) and activation of glial cells may represent some of the earliest events in the pathogenesis of DR. Upon diabetes-induced metabolic stress, abnormal glycogen synthase kinase-3β (GSK-3β) activation drives tau hyperphosphorylation and β-catenin downregulation, leading to mitochondrial impairment and synaptic neurodegeneration prior to RGC apoptosis. Moreover, glial cell activation triggers enhanced inflammation and oxidative stress, which may accelerate the deterioration of diabetic RGCs neurodegeneration. These findings have opened up opportunities for therapies, such as inhibition of GSK-3β, glial cell activation, glutamate excitotoxicity and the use of neuroprotective drugs targeting early neurodegenerative processes in the retina and halting the progression of DR before the manifestation of microvascular abnormalities. Such interventions could potentially remedy early neurodegeneration and help prevent vision loss in people suffering from DR. [Display omitted] •Neurodegeneration and neuroinflammation are early events in the development of DR.•Glial cell activation leads to enhanced inflammation, oxidative stress and mitochondrial fragmentation in early DR.•GSK-3β-driven mitochondrial impairment causes RGC synaptic neurodegeneration prior to RGC apoptosis in early DR.•Inhibitors of GSK-3β and glial cell activation, and neuroprotective drugs might be plausible pharmacotherapies in early DR.