d-arg-dmt-lys-phe-nh2 and Diabetic-Retinopathy

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.

Topics: Animals; Antioxidants; Diabetic Retinopathy; Male; Mitochondria; Oligopeptides; Rats; Rats, Long-Evans; Ubiquinone; Vision, Ocular

Diabetic retinopathy is characterized by progressive vision loss and the advancement of retinal micoraneurysms, edema and angiogenesis. Unfortunately, managing glycemia or targeting vascular complications with anti-vascular endothelial growth factor agents has shown only limited efficacy in treating the deterioration of vision in diabetic retinopathy. In light of growing evidence that mitochondrial dysfunction is an independent pathophysiology of diabetes and diabetic retinopathy, we investigated whether selectively targeting and improving mitochondrial dysfunction is a viable treatment for visual decline in diabetes. Measures of spatial visual behavior, blood glucose, bodyweight and optical clarity were made in mouse models of diabetes. Treatment groups were administered MTP-131, a water-soluble tetrapeptide that selectively targets mitochondrial cardiolipin and promotes efficient electron transfer, either systemically or in eye drops. Progressive visual decline emerged in untreated animals before the overt symptoms of metabolic and ophthalmic abnormalities were manifest, but with time, visual dysfunction was accompanied by compromised glucose clearance, and elevated blood glucose and bodyweight. MTP-131 treatment reversed the visual decline without improving glycemic control or reducing bodyweight. These data provide evidence that visuomotor decline is an early complication of diabetes. They also indicate that selectively treating mitochondrial dysfunction with MTP-131 has the potential to remediate the visual dysfunction and to complement existing treatments for diabetic retinopathy.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Oligopeptides; Ophthalmic Solutions; Sensory Thresholds; Vision, Ocular; Visual Perception

To investigate the effect of mitochondria-targeted antioxidant peptide SS31 on prevention of high glucose-induced injury on human retinal endothelial cells (HRECs).. Cultured P3-P5 HRECs were divided into three groups: 5 mM glucose group, 30 mM glucose group and 30 mM glucose co-treated with 100 nM SS31 group. 24 and 48 h after treatment, Annexin V-FITC/PI staining was used to evaluate the survival of HRECs. Overproduction of ROS was assessed by MitoSOX staining under confocal microscope. Change of mitochondrial potential (ΔΨ(m)) of HRECs was measured by flow cytometry after JC-1 fluorescent probe staining. Release of cytochrome c was assessed by confocal microscopy and western blot. Expression of caspase-3 and thioredoxin-2 (Trx-2) were measured by western blot and real-time PCR.. Compared to the high glucose group, co-treatment with 100 nM SS31 significantly protected HRECs from high glucose-induced injury, reduced the production of ROS in mitochondria, stabilized ΔΨ(m), decreased the release of cytochrome c from mitochondria to cytoplasm, decreased the expression of caspase-3 and increased the expression of Trx-2 in high glucose-treated HRECs.. SS31 attenuates the high glucose-induced injuries on HRECs by stabilizing ΔΨ(m), decreasing ROS production, preventing the release of cytochrome c from mitochondria, decreasing the expression of caspase-3 and increasing the expression of Trx-2. Our study suggests that SS31 may be as a potential new treatment for diabetic retinopathy and other oxidative stress-related diseases.

Topics: Antioxidants; Caspase 3; Caspase Inhibitors; Cells, Cultured; Cytochromes c; Diabetic Retinopathy; Endothelial Cells; Glucose; Humans; Hyperglycemia; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Proteins; Oligopeptides; Retina; Thioredoxins