DEVELOPMENT OF NEUROPROTECTIVE DRUGS FOR RETINAL DISEASE

视网膜中的神经元死亡是由缺血性损伤引起的，缺血性损伤可能由糖尿病视网膜病变、视网膜血管阻塞和可能的青光眼引起。神经元损伤的主要原因是细胞外高浓度的l -谷氨酸。视网膜中去除谷氨酸的主要机制是兴奋性氨基酸转运体EAAT1。我们的目标是确定有效的和选择性的化合物上调EAAT1的功能。这种方法是开发神经保护药物的一个尚未探索的途径。我们的方法的基础是观察到EAAT1摄取活性被溴隐亭和麦角胺增强。此外，溴隐亭在离体视网膜缺血模型中具有神经保护作用。基于这些观察结果，我们建议筛选随机小分子的大型化合物库以及基于麦角衍生物开发的用于EAAT1增强的化合物库。活性化合物将在几个已建立的模型系统中评估其选择性和神经保护作用。通过这一策略，我们将确定用于药物开发的候选分子。拟议的商业应用：这项研究有潜力鉴定出新的化合物，以减轻视网膜中神经元细胞的死亡，以应对各种疾病，包括：糖尿病视网膜病变、青光眼、视网膜静脉和动脉闭塞、前缺血性视神经病变。

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.