TARGETING SPERMINE OXIDASE TO REDUCE NEURODEGENERATION AND VISION LOSS IN DIABETIC RETINOPATHY

Abstract

Diabetic retinopathy, a major cause of vision loss, is characterized by neurodegenerative and vascular changes in the retina. Current treatments target the late phase of the disease and have undesirable side effects. Previous studies from our laboratory have shown that spermine oxidase (SMOX) is critically involved in retinal neurovascular changes. However, the molecular mechanisms of SMOX-induced neuronal damage and the impact of the long-term effects of SMOX inhibition on the diabetic retina have not been investigated yet. This present study investigated the molecular mechanisms regulated by SMOX in causing retinal neuronal damage and determined the impact of long-term inhibition of SMOX on neuro-glial injury and vision loss. Utilizing experimental models of retinal excitotoxicity, our results demonstrated upregulation in the number of microglia/macrophages in excitotoxic retinas, while MDL 72527 (a pharmacological inhibitor of SMOX) treatment reduced these changes. When retinal excitotoxicity upregulated several pro-inflammatory genes, MDL72527 treatment reduced many of them and increased anti-inflammatory genes. Furthermore, SMOX inhibition upregulated antioxidant signaling and reduced the level of conjugated acrolein in excitotoxic retinas. In vitro studies using a microglia cell line showed activated morphology and increased reactive oxygen species formation in response to the treatment with conjugated acrolein (a product of SMOX function). Streptozotocin-induced mouse model of diabetes was used to assess the effectiveness of long-term SMOX inhibition in visual acuity (VA), contrast sensitivity (CS), retinal function, and neuro-glial injury. Significant reductions in measures of VA and CS were observed in diabetic mice following 8, 16, and 24 weeks of diabetes. 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. Diabetic mice indicated marked reductions in the scotopic electroretinography (ERG) amplitudes, while MDL 72527 treatment significantly improved these reductions. Further, using neuronal and glial markers, MDL 72527 treatment reduced neuronal and glial injury in the diabetic retina, indicated by changes in neuronal and glial markers, respectively. Overall, our findings suggest that SMOX plays a critical role in retinal neurodegeneration and targeting SMOX signaling using MDL 72527 may provide a new strategy for reducing vision loss in diabetes.