Novel Short-Chain Quinones to Treat Vision Loss in a Rat Model of Diabetic Retinopathy.

Abraham Daniel,Krupali Shah,Jason A Smith,Krystel L Woolley,Nicole Bye,Zikai Feng,Qianyi Zhang,Lisa Foa,Dino Premilovac,Nuri Gueven

doi:10.3390/ijms22031016

Abraham Daniel, Krupali Shah + Show 8 more

Open Access

https://doi.org/10.3390/ijms22031016

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Abstract

Diabetic retinopathy (DR), one of the leading causes of blindness, is mainly diagnosed based on the vascular pathology of the disease. Current treatment options largely focus on this aspect with mostly insufficient therapeutic long-term efficacy. Mounting evidence implicates mitochondrial dysfunction and oxidative stress in the central etiology of DR. Consequently, drug candidates that aim at normalizing mitochondrial function could be an attractive therapeutic approach. This study compared the mitoprotective compounds, idebenone and elamipretide, side-by-side against two novel short-chain quinones (SCQs) in a rat model of DR. The model effectively mimicked type 2 diabetes over 21 weeks. During this period, visual acuity was monitored by measuring optokinetic response (OKR). Vision loss occurred 5–8 weeks after the onset of hyperglycemia. After 10 weeks of hyperglycemia, visual function was reduced by 65%. From this point, the right eyes of the animals were topically treated once daily with the test compounds. The left, untreated eye served as an internal control. Only three weeks of topical treatment significantly restored vision from 35% to 58–80%, while visual acuity of the non-treated eyes continued to deteriorate. Interestingly, the two novel SCQs restored visual acuity better than idebenone or elamipretide. This was also reflected by protection of retinal pathology against oxidative damage, retinal ganglion cell loss, reactive gliosis, vascular leakage, and retinal thinning. Overall, mitoprotective and, in particular, SCQ-based compounds have the potential to be developed into effective and fast-acting drug candidates against DR.

Highlights

Diabetic retinopathy (DR) is a microvascular, neurodegenerative disease, as a complication of chronic hyperglycemia, and clinically manifests as progressive vision loss [1]
When visual function of the treatment groups (Figure 1b–f) was compared against nondiabetic rats (Figure 1a), visual acuity declined for all treatment groups between Weeks 9 and 14 (Figure 1a–f, graphs separated for clarity)
#37 and elamipretide significantly protected againstmonitoring oxidative damage asdi‐

Summary

Introduction

Diabetic retinopathy (DR) is a microvascular, neurodegenerative disease, as a complication of chronic hyperglycemia, and clinically manifests as progressive vision loss [1]. In the early stages of DR, most patients remain asymptomatic, but as the disease progresses, visual symptoms such as eye floaters, blurred vision, and visual distortion manifest [2]. Intravitreal administration of corticosteroids and antivascular endothelial growth factor (anti-VEGF) therapy, laser photocoagulation, and vitrectomy are used to treat DR, depending on the pathology and stage of the disease [5]. While treatments such as intravitreal steroids and anti-VEGF agents represent successful first-line treatments against inflammation and angiogenesis associated with DR [6,7], their invasive mode of administration remains unattractive [5,8]. Most therapies are only beneficial in the progressive stage of DR [5,9], with fewer treatment options for nonproliferative

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