Deletion of 12/15-Lipoxygenase Preserves Retinal Neuronal Function in Diabetic Retinopathy

Abstract

Purpose: Diabetic retinopathy (DR) is a neurovascular complication of diabetes with critical limitations in current treatment due to a lack of neuroprotection. These limitations mandate the necessity for new therapy that considers the neuronal component of DR. The goal of this study is to explore the role of 12/15-lipoxygenase (LO) in diabetes-induced retinal neuronal dysfunction. Methods: 12/15-LO deficient (12/15-LO−/−) mice were crossbred with Ins2Akita/+ Akita) mice, a classical model of DR, to generate a new mouse model with a double knockout (12/15-LO−/−/Akita). The generated mice were subjected to comprehensive electroretinogram (ERG) analyses after 6 months of diabetes. Results: Profound effects of knocking 12/15-LO out on diabetes-induced reduction in visual system’s functionality were observed. First, Scotopic Threshold Response (pSTR) peak heights, which measure the functionality of ganglion cells (GCs), are consistently lower in Akita than in wild type (WT) mice. Knocking 12/15-LO out significantly improved the overall pSTR and significantly restored the loss of the GC marker (Brn3) as compared with Akita mice. Second, diabetes reduced the functionality of cone-bipolar cells by 32%, as assessed by photopic B-Wave (pBW) amplitudes, however, this reduction was significantly improved in 12/15-LO−/−/Akita mice compared with Akita mice (p<0.05, n=9). Lastly, diabetes caused a significant reduction (22%) in cone photoreceptor functionality as indicated by a lower response to natural noise stimuli (NNS) in Akita compared to WT mice (p<0.05, n=8) and this reduction was completely recovered in 12/15-LO−/−/Akita mice (p<0.05, n=9). Conclusion: To our knowledge, this is the first report that elimination of 12/15-LO protects against diabetes-induced visual system dysfunction. The findings may lead to new therapeutic approaches in prevention and treatment of DR. Disclosure M. Wan: None. A. Ibrahim: None. M. El-Shafey: None. K. Elmasry: None. S. Abdulmoneim: None. A. Saul: None. M. Al-Shabrawey: None.