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 Applications

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43EY012742-01A1
Application #
6140451
Study Section
Special Emphasis Panel (ZRG1-VISA (02))
Program Officer
Dudley, Peter A
Project Start
2000-04-01
Project End
2000-09-30
Budget Start
2000-04-01
Budget End
2000-09-30
Support Year
1
Fiscal Year
2000
Total Cost
$99,390
Indirect Cost
Name
Neurocrine Biosciences, Inc.
Department
Type
DUNS #
800981276
City
San Diego
State
CA
Country
United States
Zip Code
92130