DEVELOPMENT OF NEUROPROTECTIVE DRUGS FOR RETINAL DISEASE

点击翻译按钮获取中文摘要

Neuronal death in the retina results from ischemic damage which may arise from such conditions as diabetic retinopathy, retinal vasculature obstructions, and possibly glaucoma. A primary cause of neuronal damage is high extracellular concentrations of L-glutamate. The central mechanism for removing glutamate in the retina is the excitatory amino acid transporter EAAT1. Our goal is to identify potent and selective compounds that upregulate EAAT1 function. This approach is an unexplored avenue for the development of neuroprotective drugs. Underlying our approach is the observation that EAAT1 uptake activity is enhanced by bromocriptine and ergotamine. Furthermore, bromocriptine is neuroprotective in an ex vivo retinal ischemia model. Based on these observations, we propose to screen both a large compound library of random small molecules as well a- a compound library that we will dcv9lop based on ergot derivatives for EAAT1 enhancement. Active compounds will be assessed for selectivity and neuroprotection in several established model systems. Through this strategy, we will identify a candidate molecule for medicinal development. PROPOSED COMMERCIAL APPLICATION: This research has the potential to identify novel compounds for the alleviation of neuronal cell death in the retina in response to a wide range of conditions including: diabetic retinopathy, glaucoma, venous and arterial occlusions of the retina, and anterior ischemic optic neuropathy.