Abstract
Purpose :
Diabetic retinopathy, a major cause of vision loss, is characterized by neurodegenerative changes in the retina. A previous study from our laboratory demonstrated that 12-week treatment with MDL 72527, a pharmacological inhibitor of spermine oxidase (SMOX, an inducible enzyme of polyamine oxidation pathway), reduced neuronal damage and improved retinal function in diabetic mice. The current study was undertaken to assess the effectiveness of long-term SMOX inhibition in visual acuity (VA), contrast sensitivity (CS), retinal function, and neuro-glial injury in diabetic mice.
Methods :
Diabetes was induced in male mice (C57BL6J, 8-10 weeks old) with multiple injections of streptozotocin (65 mg/kg). Mice with blood glucose higher than 350mg/dL were considered diabetic and maintained 24 weeks post-diabetes. Animals (diabetic or controls) were treated with MDL 72527 (20 mg/kg) or saline three times a week. Body weight and blood glucose were measured weekly, and HbA1c was tested every eight weeks. Mice were evaluated for VA and CS (optokinetic tracking response, every 8 weeks) and retinal function (electroretinography, 24 weeks). Retinal cryostat sections and fresh frozen retinas were used for immunofluorescence and western blot studies. Statistical analyses were performed using GraphPad Prism 9.
Results :
Significant reductions in measures of VA and CS were observed in diabetic mice following 8, 16, and 24 weeks (N=15-17, P<0.01). However, treatment with MDL 72527 improved both VA and CS at all the time points studied, with a significant increase at 24 weeks post-diabetes (N=13-15, P<0.05). In comparison with control mice, marked reductions in scotopic b-amplitudes (at 0.01, 0.05, 0.1, 0.5, and 1.0 cd.s/m2) were observed in diabetic mice (N=10-12; P<0.01). MDL 72527-treated diabetic mice showed significantly improved b amplitudes (N=9-12; P<0.05) at all intensities, suggesting protection of inner retinal function. Diabetes-induced decreases in synaptophysin and glutamine synthetase and the increase in vimentin levels were reversed in response to SMOX inhibition (N=3-4). Results were comparable between non-diabetic saline-treated group and non-diabetic MDL 72527-treated group.
Conclusions :
Our findings suggest that targeting SMOX signaling may provide a new strategy for reducing vision loss in diabetes.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.