Neuroprotective strategies for retinopathy and cognition in diabetes

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Over 25 million U.S. citizens (8.3% of the population) have diabetes, including 20% of veterans in the VA system. With the worldwide prevalence of diabetes predicted to rise 35% by 2025, diabetic complications impose an ever-increasing burden on healthcare systems. One of the most common complications, diabetic retinopathy (DR), is the leading cause of blindness in working age adults. In addition, early neuronal dysfunction in diabetic retinopathy occurs prior to clinically diagnosable pathology, and early DR is likely intimately related to other diabetic complications, for example, cognitive decline and structural changes in the brain. The continued rise in the number of diabetic patients and the complexity of their care underscores the urgent need to identify clinically translatable treatments to target complications prior to obvious signs and symptoms. While diabetes is not commonly thought of as a disease of dopamine disruption, dopamine has been implicated in several diabetic complications, including diabetic retinopathy. Our approach is to identify whether dopamine deficiency is a common mechanism for cerebral and retinal deficits in Type II diabetes and to use this information to develop dopamine treatments for long term clinical translation that would delay disease progression. In this study, we will use the high fat diet + low dose STZ rat model of Type II diabetes because approximately 90% of diabetic patients in the VA system have Type II diabetes. We hypothesize that: 1) dopamine disruption underlies both retinal and cerebral complications in diabetes, and 2) dopamine- targeted treatments will result in reduced retinal, cognitive, and motor dysfunction and reduced vascular pathology in the brain and retina. In the first specific aim, we will identify in Type II diabetic rats the temporal appearance of retinal dysfunction (electroretinogram, optokinetic tracking), cognitive dysfunction (y-maze), motor dysfunction (rotarod), retinal vascular dysfunction (functional hyperemia), and later stage vascular pathology (acellular capillaries and pericyte loss), as well as retinal and brain levels of dopamine and DOPAC (HPLC). After determining the time course of these deficits, in the second specific aim, we will implement L- DOPA treatment to reduce dopamine deficiency in diabetic rats. We will determine whether rats receiving treatment exhibit reduced dopamine deficiency and reduced retinal, cognitive, and motor dysfunction. In our third specific aim, we will use a retrospective chart review in a large dataset to determine whether diabetic patients taking levodopa or dopamine agonists exhibit delayed onset and progression of DR compared with diabetic patients not taking dopamine-related drugs. The expected outcome of this study is that L-DOPA treatment given at the earliest signs of retinopathy in a rodent model of Type II diabetes will provide protection against diabetic damage in the brain and retina and that L-DOPA/dopamine agonists will provide similar protection against DR in patients. Our rodent research can lead to the identification of a similar window for preclinical retinopathy treatment in diabetic patients, which would allow for greater treatment efficacy and prevention of future complications. If treatments that target dopamine protect against retinal and cerebral complications in diabetes, these findings would motivate the development of a human clinical trial. Overall, the motivation for this study is the need for a better understanding of the role of dopamine in diabetic retinopathy and other diabetic complications with the long-term goal of developing dopamine-targeted treatments that delay or prevent vision loss and cerebral deficits in our Veterans and others with diabetes. The Atlanta VA has a large population of diabetic patients and already performs clinical diabetes research, making a long term clinical study on dopamine treatment in diabetes a natural fit for the Center’s goals and interests. This research will also provide valuable training to the applicant, which will enable her to become a successful and productive independent investigator in the field of the diabetic brain and retina within the VA research environment.