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

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.

Cytoprotective Effect of Idebenone through Modulation of the Intrinsic Mitochondrial Pathway of Apoptosis in Human Retinal Pigment Epithelial Cells Exposed to Oxidative Stress Induced by Hydrogen Peroxide

“…IDB’s effects have been investigated in both pre-clinical and clinical trials for the treatment of Alzheimer’s disease [ 3 , 4 , 5 ] and cognitive-behavioral deficits of vascular and degenerative origin [ 6 , 7 ], as well as for therapies for some rare hereditary pathologies characterized by mitochondrial damage, such as Duchenne muscular dystrophy and Friedreich ataxia, with mixed success [ 8 , 9 , 10 ]. The marketing authorization of Raxone ® (a drug containing the active ingredient IDB) for the treatment of Leber’s hereditary optic neuropathy (LHON) [ 11 ], a neurodegenerative disease of the optic nerve characterized by the sudden loss of vision in adults and adolescents, rekindled the spotlight on IDB and its possible therapeutic role in various ophthalmic diseases, especially those with a close connection between low vision and mitochondrial dysfunction [ 12 , 13 ].…”

Development and characterisation of a rat model that exhibits both metabolic dysfunction and neurodegeneration seen in type 2 diabetes

“…In the present study, we attempted to quantify vision loss across in animals exposed to HFD + lower and HFD + higher STZ using the optokinetic reflex as reported previously (Daniel et al . 2021). However, because Sprague–Dawley rats are an albino strain, they inherently have poor visual acuity.…”

“…Lastly, we wanted to assess whether our type 2 diabetic animals also develop signs of diabetic retinopathy, a leading cause of blindness worldwide (Bourne et al 2013;Lee et al 2015;Zafar et al 2019). Unfortunately, because we utilised an albino rat strain in our experiments, we were unable to directly assess changes in visual acuity across our experiment as previously published (Daniel et al 2021). Nevertheless, we collected eyes from all animals at the end of the time course and used histological techniques to assess changes in the retina as previously described.…”

“…The different layers of the retina were identified using DAPI staining as reported previously (Daniel et al . 2021). The density of retinal ganglion cells (RGCs) was determined by counting the number of Brn3a positive cells in the RGC layer of the retina and expressed as cells per millimetre 2 .…”

Short-Chain Naphthoquinone Protects Against Both Acute and Spontaneous Chronic Murine Colitis by Alleviating Inflammatory Responses

“…Among them, 16 amide-linked naphthoquinones showed high metabolic stability, low toxicity, and better cytoprotection in vitro ( Woolley et al, 2019 ; Feng et al, 2020a ; Feng et al, 2020b ). Indeed, one of the newly synthesised naphthoquinones (UTA77) restored vision loss in vivo in mitochondrial dysfunction-related pathology, i.e., diabetic retinopathy ( Daniel et al, 2021 ).…”